Regulation of Electroneutral NaCl Absorption by the Small Intestinepc › ~petesmif › petesmif ›...

PH73CH12-Romero ARI 3 January 2011 16:27

Regulation of ElectroneutralNaCl Absorption by theSmall IntestineAkira Kato1,2 and Michael F. Romero2,3,4

1Biological Sciences, Tokyo Institute of Technology, Yokohama 226-8501, Japan;email: [email protected] & Biomedical Engineering, 3Nephrology & Hypertension, and 4O’BrienUrology Research Center, Mayo Clinic College of Medicine, Rochester, Minnesota 55905;email: [email protected]

Annu. Rev. Physiol. 2011. 73:261–81

First published online as a Review in Advance onNovember 5, 2010

The Annual Review of Physiology is online atphysiol.annualreviews.org

This article’s doi:10.1146/annurev-physiol-012110-142244

Copyright c© 2011 by Annual Reviews.All rights reserved

0066-4278/11/0315-0261$20.00

Keywords

NHE, SLC26, NHERF, CFTR, neuroendocrine system

Abstract

Na+ and Cl− movement across the intestinal epithelium occurs by sev-eral interconnected mechanisms: (a) nutrient-coupled Na+ absorption,(b) electroneutral NaCl absorption, (c) electrogenic Cl− secretion byCFTR, and (d ) electrogenic Na+ absorption by ENaC. All these trans-port modes require a favorable electrochemical gradient maintainedby the basolateral Na+/K+-ATPase, a Cl− channel, and K+ chan-nels. Electroneutral NaCl absorption is observed from the small in-testine to the distal colon. This transport is mediated by apical Na+/H+

(NHE2/3) and Cl−/HCO3− (Slc26a3/a6 and others) exchangers that

provide the major route of NaCl absorption. Electroneutral NaCl ab-sorption and Cl− secretion by CFTR are oppositely regulated by theautonomic nerve system, the immune system, and the endocrine systemvia PKAα, PKCα, cGKII, and/or SGK1. This integrated regulation re-quires the formation of macromolecular complexes, which are mediatedby the NHERF family of scaffold proteins and involve internalizationof NHE3. Through use of knockout mice and human mutations, amore detailed understanding of the integrated as well as subtle regula-tion of electroneutral NaCl absorption by the mammalian intestine hasemerged.

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Cystic fibrosistransmembraneconductanceregulator (CFTR): aCl− channel mutatedin cystic fibrosis; anABC transporter

ENaC: epithelial Na+channel

Slc#/SLC#: HUGOnomenclature forsolute carrier. The #symbol indicates genefamily; all-capitalformatting is specificto human genes

INTRODUCTION

The mammalian intestine is responsible forthe digestion and absorption of ingested food.However, the secretion and absorption of elec-trolytes and fluid are also essential functionsof the intestine, in particular of intestinal ep-ithelial cells. In humans, the gastrointestinal(GI) tract secretes 8–10 liters day−1 of fluidin the face of ingested food containing 1.5–2 liters day−1 of fluid. Most fluid is (re)absorbedby the small intestine (∼95%) and large in-testine (∼4%) of the GI tract. The small in-testine secretes ∼1 liter day−1 and (re)absorbs∼6.5 liters day−1, making it the major netfluid absorber. Because there is no active wa-ter movement in the human body, GI epithe-lial cells drive fluid movement through activemovement of Na+ and Cl− (discussed in thisreview) or HCO3

− (beyond the scope of this re-view). In the intestine, there are four modes ofNa+ and Cl− movement: (a) nutrient-coupledNa+ absorption, (b) electroneutral NaCl ab-sorption, (c) electrogenic Cl− secretion by thecystic fibrosis transmembrane conductance reg-ulator (CFTR), and (d ) electrogenic Na+ ab-sorption by the epithelial Na+ channel (ENaC).The four modes mentioned here are describedin detail in the following paragraphs.

Nutrient-Coupled Na+ Absorption

In the 1960s, transepithelial sugar and aminoacid movement was measured using the short-circuit current technique (the Ussing cham-ber). These studies found that absorption is de-pendent on extracellular (luminal) Na+. Thisnutrient-coupled Na+ absorption is now ex-plained by the function of Na+/glucose-linkedtransporters (SGLTs, also known as Slc5 pro-teins), several Na+/amino acid cotransporters(Slc6, Slc38, etc.), and Na+-coupled solutecarriers (see http://www.bioparadigms.org/slc/menu.asp). The transepithelial Na+ move-ment generates a lumen-negative (mucosa-negative) transepithelial voltage facilitatingparacellular Cl− and fluid absorption. This ab-sorption can be regulated by enterotoxins and

is thus also used as a route for therapeuticallyincreasing Na+ absorption via oral rehydration.

Electroneutral NaCl Absorption

During the 1960s to 1980s, short-circuit-current studies also demonstrated that the smallintestinal and proximal colonic mucosa hasbasal NaCl and fluid absorption in the absenceof nutrients and is not associated with transep-ithelial currents (Figure 1a). These findingswere in contrast to other modes of Na+ andCl− transport, all of which caused transepithe-lial currents. Therefore, this absorption mode istermed electroneutral NaCl absorption. Thesestudies demonstrated that the coupled func-tion of an apical Na+/H+ exchanger(s) anda Cl−/HCO3

− exchanger(s) mediates absorp-tion, the details of which are highlighted in thisreview.

Electrogenic Cl− Secretion

When the intestinal mucosa (apical or luminalsurface) is stimulated by agents that increaseintracellular cyclic AMP (cAMP), Ca2+, orcyclic GMP (cGMP), electroneutral NaClabsorption is inhibited, and Cl− secretion isactivated (1) (Figure 1b). Apical Cl− channelCFTR mediates such secretion (2). The insidenegative electric potential of epithelial cellsprovides the driving force to secrete Cl−. Thismovement generates a lumen-negative electri-cal difference that results in paracellular Na+

secretion, and CFTR-mediated electrogenicCl− secretion occurs in all regions of the smalland large intestines.

Electrogenic Na+ Absorption

Electrogenic Na+ absorption (3, 4), a rheogenicmode, is specific to the distal colon. Here thetransepithelial electrical resistance is higherthan that of other GI segments. Colonictransepithelial voltage (Vt) exceeds −20 mV.In the colon, luminal Na+ is much lower thanin other segments and decreases in a proximal-to-distal manner. This lumen-negative

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––

–

a

CO2 + H2O

c

Lumen

Ion

flux

(μ E

q h–1

) Na+ Cl–

Na+ Cl–

Secr

etio

n

Abs

orpt

ion

Sec

Abs

Sec

Abs

Sec

Abs

Cl–Na+

26a3

Cl–Cl–

HCO

3 –

CA

NH

E3

H+

Na+

26a6

Cl–

K+

Kir7.1

26a9

Cl–

Cl–Cl–

26a9

Cl–

Cl– Na+

Slc26a9

Cl–

CFTR

ATP ADPNKA

K+K+

ClC-2

Cl–

RSR RR

NHERF NHERF NHERF NHERF

?+

+

+

+

Lumen 26a3

NH

E3

CFTR

S

26a6

S

26a9

CFTR CFTR CFTR

Cl–ElectroneutralNaCl absorption

Cl–Na+ ElectrogenicCl– secretion

Cl–

Abs

orpt

ion

Secr

etio

n

20

15

10

5

0Basal cAMP

Basal cAMP

–5

0

5

Net

ion

flux

(μ E

q h–1

)

b

Na+ Na+

Na+

Figure 1Mechanism of electroneutral NaCl absorption by intestinal epithelial cells. (a) Measurement of electroneutral NaCl absorption andcyclic AMP (cAMP)-stimulated, electrogenic Cl− secretion. The basal (upper left) and cAMP-stimulated (upper right) transepithelialmovement of Na+ and Cl− by rabbit ileal mucosa (1.12-cm2 exposed area) was measured by the short-circuit technique (using Ussingchambers). Mucosal → serosal [absorption (abs)] movement and serosal → mucosal [secretion (sec)] movement are both shown. Netion flux is shown in the lower graph of panel a: Positive values indicate net absorption, and negative values indicate net secretion.Modified with permission from Field (69). (b) Molecules involved in electroneutral NaCl absorption. A Na+/H+ exchanger (NHE3)and anion exchangers (Slc26a3/6/9) mediate apical absorption of NaCl. Na+/K+-ATPase (NKA) and ClC-2 chloride channel mediatebasolateral movement of NaCl. Metabolic CO2 is the source of H+ and HCO3

− ions via intracellular carbonic anhydrase II (CA)catalysis. Cystic fibrosis transmembrane conductance regulator (CFTR) mediates electrogenic Cl− secretion. (c) Direct or NHE-regulatory factor (NHERF)-mediated interaction between CFTR and transporters. Known interactive activation (+) and inhibition (−)are shown; the question mark denotes that whether the interaction is activating or inhibiting is unknown. R, R-region of CFTR;S, STAS (sulfate transporter antisigma domain) of Slc26s.

NHE: Na+/H+exchanger

Slc26a3:a Cl−/HCO3

−exchanger

DRA: downregulatedin adenoma

Vt provides the thermodynamic driving forcethat allows the mucosa to absorb Na+ againsta large Na+ concentration gradient. ENaC(5), which is regulated predominantly byaldosterone (6), mediates such Na+ absorption.

In the early 1990s, two mammalianNa+/H+ exchangers, NHE2 (Slc9a2) andNHE3 (Slc9a3), were identified as moleculesthat are expressed predominantly in the api-cal membrane of intestinal and renal epithe-lium. At least two mammalian Cl−/HCO3

−

exchangers, Slc26a3 [downregulated in ade-noma (DRA)] and Slc26a6 [putative aniontransporter-1 (PAT-1)], are highly expressedin the apical membrane of intestinal epithe-lium (Figure 1c). Investigators recently locatedSlc26a9, which is an nCl−/HCO3

− exchangerand Cl− channel (7), at the apical membrane ofthe small intestine and colon (8). In the 2000s,knockout mice for Nhe2, Nhe3, Slc26a3, andSlc26a6 were studied, and their roles in vivowere analyzed. Initial analysis of Slc26a9−/−

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Slc26a6:an electrogenicCl−/nHCO3

−exchanger; also knownas PAT1 or CFEX;exchanges Cl− forHCO3

−, sulfate,oxalate, or formate;activated by theR-region of CFTR

Slc26a9:an electrogenicnCl−/HCO3

−exchanger; a Cl−channel andNa+/anioncotransporter;inhibited by theR-region of CFTR

Na+/K+-ATPase(NKA): a Na+ pump

mice shows defective stomach acid secretion (9),but such mice have not been assessed for in-testinal absorption phenotypes. In this review,we describe the function and the regulation ofthese transporters, particularly in relation toelectroneutral NaCl absorption in the mam-malian small intestine.

MOLECULES INVOLVED INELECTRONEUTRAL NaClABSORPTION BY THESMALL INTESTINE

NHE2 and NHE3: Na+/H+

Exchangers for Apical Na+ Absorption

Na+/H+ exchange mediates luminal Na+

absorption by the small intestine. TwoNa+/H+ exchangers, NHE2 (Slc9a2) andNHE3 (Slc9a3), are localized to the intesti-nal brush border membrane. Intestinal expres-sion and function of NHE2 and NHE3 sig-nificantly overlap. Analyses of Nhe2−/− andNhe3−/− mice demonstrate that NHE3 is thedominant Na+/H+ exchanger in the smallintestine.

Slc9 is a family of Na+/H+ exchangers thatconsists of eight membrane proteins (10, 11).NHE2 (12, 13) and NHE3 (14, 15) were firstidentified as NHE1 homologs, and their tran-scripts are highly expressed in the GI tract(stomach, small intestine, large intestine) andthe kidney. In contrast to NHE1 at the basolat-eral membrane, NHE2 and NHE3 are found atthe brush border (apical) membrane of the in-testinal epithelium (jejunum, ileum, and colon)and at the renal tubule (proximal tubule andthick descending limb of Henle’s loop). NHE2and NHE3 activity has been studied by express-ing the recombinant proteins in NHE-null celllines (PS120 or SP-1). Both NHE2 and NHE3mediate Na+/H+ exchange with a stoichiom-etry of 1Na+:1H+ (16). The inward Na+ gra-dient (low intracellular [Na+]) maintained bythe basolateral Na+/K+-ATPase (NKA) pro-vides the continuous driving force.

NHE3 is important for normal GI phys-iology. Nhe3−/− mice have slight diarrhea,

mild acidosis, reduced blood pressure, andincreased intestinal segment size and weight(17). The contents of the small intestine, ce-cum, and colon of Nhe3−/− mice are some-what alkaline (17). In the kidney, proximaltubule fluid and HCO3

− absorption are sig-nificantly reduced in Nhe3−/− mice (17). TheNhe3−/− jejunum exhibits reduced Na+ absorp-tion (18). Apical membrane Na+/H+ exchangeactivity of jejunal, midvillous epithelium is de-creased in Nhe3−/− mice (19). In the colon ofNhe3−/− mice, ENaC and H+/K+-ATPase ex-pression are upregulated. These alterations in-crease amiloride-inhibitable short-circuit cur-rent. Thus, electrogenic Na+ absorption byENaC compensates for NHE3 loss of func-tion (17). 3-Methylsulfonyl-4-piperidino ben-zoyl guanidine methanesulfonate (HOE-694)is an inhibitor of NHEs, with NHE2 IC50 of3–5 μM and NHE3 IC50 of 650 μM. HOE-694 was used to quantify the contribution ofNHE2 and NHE3 to rabbit ileal brush bor-der NHE activity (20). Under basal conditions,both NHE2 and NHE3 contributed ∼50% tothe total NHE activity. In contrast, glucocor-ticoids stimulated only NHE3 activity (by 4.1times) but not NHE2 activity. NHE3 can com-pensate for NHE2 intestinal function (21–23),but NHE2 cannot compensate for intestinalNHE3 function.

Apical Cl−/HCO3− Exchangers:

Slc26 Proteins

Cl−/HCO3− exchange mediates luminal Cl−

absorption by the small intestine. Thus far, twoCl−/HCO3

− exchangers have been localized tothe intestinal brush border membrane. TheseCl−/HCO3

− exchangers, Slc26a3 and Slc26a6,are not related to the band 3 Cl−/HCO3

−

exchangers (AE1–3) but rather belong to theSlc26 family. Intestinal expression of Slc26a3and Slc26a6 overlaps (24). Melvin et al. (25)were the first to show that a Slc26 protein,i.e., Slc26a3, functions as a Cl−/HCO3

− ex-changer. Later, Slc26a6 was shown to func-tion as an electrogenic Cl−/nHCO3

− exchanger(26–29). Muallem’s group found the Slc26a3 is

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Cl−-losing diarrhea(CLD): activated bythe R-region of CFTR

also electrogenic and has the opposite couplingof Slc26a6 (27, 29). Recent analyses of Slc26a3-null (Slc26a3−/−) and Slc26a6-null (Slc26a6−/−)mice demonstrated that both transporters havesignificant roles in Cl− absorption and HCO3

−

secretion by the intestine (19, 24, 30). Slc26a3and Slc26a6 have significant roles in unstim-ulated HCO3

− secretion by the duodenum,but Slc26a6 is more predominant. In contrast,Slc26a3 plays a more significant role duringcAMP-stimulated duodenal HCO3

− secretion.In the jejunum, Slc26a3 and Slc26a6 have sig-nificant roles in Cl− absorption; however, hereSlc26a3 is more abundant. Slc26a6 also playssignificant roles in duodenum SO4

2− absorp-tion and oxalate excretion (26, 31–35). Finally,Slc26a3 is important for colonic Cl− absorption(36, 37).

Slc26 is an anion transporter and com-poses a channel family with 10 gene mem-bers (8, 28, 35). Slc26 proteins transport mono-valent anions [Cl−, iodide, formate, oxalate,hydroxyl ion (OH−), and HCO3

−] and diva-lent anions (SO4

2− and oxalate) (38). SLC26A3was first identified in the colon, and its ex-pression is downregulated in colonic adeno-mas (DRA) (39). The SLC26A3 transcript isexpressed in the intestine from the duodenumto the distal colon but is most abundant inthe duodenum and the colon. Immunohisto-chemical analyses demonstrated that Slc26a3is localized to the apical membrane of ente-rocytes of surface and crypt in the colon (35,36, 40) and the apical membrane of the pancre-atic duct (41). When exogenously expressed inXenopus oocytes and mammalian culture cells,Slc26a3 mediates electrogenic Cl−/nHCO3

−

and Cl−/nOH− exchange with a stoichiometryof 2Cl−:1HCO3

− (29).SLC26A6 was first identified through

database mining and named PAT-1 (42). Itsanion transport activity was later established(26, 31, 43, 44). In contrast to SLC26A3mRNA (which is expressed mainly in the intes-tine), SLC26A6 transcripts are expressed in thesmall intestine as well as the kidney, pancreas,heart, and placenta. In the intestine, Slc26a6 ismost abundant in the duodenum, jejunum, and

ileum, with lower expression in the colon. Im-munohistochemical analyses demonstrated thatSlc26a6 is localized at the apical membrane ofgastric parietal cells (45) and duodenal entero-cytes (44), as well as the apical membrane of therenal proximal tubule (43, 46). When exoge-nously expressed in Xenopus oocytes and mam-malian culture cells, Slc26a6 mediates electro-genic Cl−/nHCO3

−, Cl−/nOH−, Cl−/oxalate,and Cl−/SO4

2− exchange, as well as electroneu-tral Cl−/formate and SO4

2−/oxalate exchange.The stoichiometry of Cl−/HCO3

− exchangeby Slc26a6 is 1Cl−:2HCO3

− (29, 47), which isthe opposite of the stoichiometry of such ex-change by Slc26a3 (29). This coupling issuehas been questioned by one research group thatfound electrogenic Cl−/oxalate2− exchange formouse Slc26a6 but electroneutral Cl−/HCO3

−

exchange for mouse Slc26a6 as well as humanSLC26A6 (48).

In humans, recessive loss-of-function mu-tations in the SLC26A3 gene result in severecongenital Cl−-losing diarrhea (CLD) (49). Be-cause SLC26A3 mutations cause CLD, thisSlc26a3 exchanger is crucial for NaCl absorp-tion in the colon. Accordingly, Slc26a3−/− miceexhibit high-chloride-content diarrhea (36).Apical Cl−/OH− and Cl−/HCO3

− exchangeactivity is significantly decreased in the colon ofSlc26a3−/− mice, and luminal content is moreacidic in the Slc26a3−/− colon. These obser-vations also suggest that Slc26a3 is the majorcolonic Cl−/base exchanger (36). In addition tothe colon, Cl− absorption is essentially abol-ished in the jejunum of Slc26a3−/− mice (19).Basal Cl−/HCO3

− exchange activity is also re-duced by 30–40% in the Slc26a3−/− duode-num (50). Unstimulated and cAMP-stimulatedHCO3

− secretions in the Slc26a3−/− duode-num are reduced by ∼55–60% and ∼50%, re-spectively, in the duodenum of Slc26a3−/− mice(51).

Slc26a6 knockout mice develop a high in-cidence of calcium oxalate urolithiasis (34).Duodenal oxalate efflux is significantly reducedin Slc26a6-null mice (32), which results inincreased dietary oxalate absorption and in-creased oxalate concentration in plasma and


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STAS: sulfatetransporter antisigmadomain

urine (34). In the Slc26a6−/− mouse duodenum,basal HCO3

− secretion and Cl− absorption aresignificantly decreased, yet cAMP-stimulatedHCO3

− secretion is not altered compared withwild-type mice (32, 52). Basal Cl−/HCO3

− ex-change activity is reduced by 65–80% in theSlc26a6−/− duodenum; this reduction is moresevere than that of Slc26a3−/− mice. In addi-tion, SO4

2−/HCO3− exchange activity is almost

abolished in the Slc26a6−/− duodenum. In theSlc26a6−/− jejunum, Cl− absorption seems de-creased (30), but other work found that the re-duction of jejunal Cl− absorption in Slc26a6−/−

mice is much less than that of Slc26a3−/− mice(19). In isolated, microperfused renal tubules ofSlc26a6−/− mice, apical Cl−/HCO3

− exchangeractivity is reduced (32).

The intestinal Cl− absorption deficiency inSlc26a3−/− mice is more severe than that ofSlc26a6−/− mice, even though both Slc26a3 andSlc26a6 are highly expressed in the intestineand have high Cl−/HCO3

− exchange activityin vitro. These results suggest that Slc26a3 cancompensate for Slc26a6’s role in intestinal Cl−

absorption, whereas Slc26a6 cannot compen-sate for Slc26a3 in the small intestine or thecolon in electrogenic NaCl absorption. Con-versely, only Slc26a6−/− mice have defectiveduodenum SO4

2− and oxalate transport, sug-gesting that Slc26a3 cannot compensate forthese functions. These mouse physiological re-sults are not surprising because neither SO4

2−

nor oxalate is a substrate for Slc26a3-mediatedexchange (28).

Slc26a9 is another anion transporter inthe GI tract (53) with functional multiplicity(Figure 1): It is an nCl−/HCO3

− exchanger,a Cl− channel, and a Na+/anion cotransporter(7). As for Slc26a3 and Slc26a6, Slc26a9 is alsolocalized to the apical pole of epithelial cells(7, 47, 53, 54). Interaction with the R-regionof CFTR and the Slc26-STAS domain stimu-lates the activity of Slc26a3/a6 (27) (Figure 1c).Interestingly, this same STAS/R-region inter-action leads to inhibition of Slc26a9 activity(Figure 1c) (55). Slc26a9−/− mice have poorstomach acid secretion and loss of tubulovesi-cles in parietal cells (9). Although Slc26a9 is

present in the small intestine (53), Slc26a9−/−

mice do not have an obvious intestinal pheno-type. This scenario makes sense, as Slc26a9 inthe intestine is secondary to CFTR Cl− chan-nels as well as Slc26a3/a6. Nonetheless, be-cause Slc26a9 has opposite interaction regu-lation, Slc26a9 activity may be unchecked inthe absence or misdirection of CFTR. This ofcourse would affect the severity of intestinal cys-tic fibrosis phenotypes.

Basolateral Transport

Although apical transporters and channels inthe intestine have been the subject of in-tense recent study, the basolateral (serosal,or blood-side) transporters and channels areequally important. That said, details of basolat-eral transport in NaCl absorption are limited.Figure 1a illustrates that once Na+ and Cl− areapically absorbed, a functional combination ofa Cl− channel (ClC-2) (56–59), NKA, and a K+

channel (Kir 7.1) (60, 61) are the major play-ers in the basolateral step. Moreover, ClC-2is necessary (in the jejunum) to recover para-cellular permeability (barrier function) afterischemia (62) and is associated at lateral mem-branes with villus and tight junction function(63). Clinically, lubiprostone (SPI-0211, a Cl−

channel activator) is used to treat (reverse) con-stipation (64). Lubiprostone activates intestinalClC-2 channels (65) but in some circumstancesalso requires CFTR function (66). The role ofCFTR, however, is controversial (67). ClC-2can be turned down by α1-adrenergic nerves(68). The K+ channel (presumably Kir 7.1) isneeded to recycle K+ after the NKA exchanges2K+ for 3Na+ to complete the NaCl blood-exitstep (Figure 1a).

REGULATION OF IONTRANSPORTERSIN EPITHELIAL CELLS

In the epithelial cells of the small intes-tine and proximal colon, intracellular sec-ond messengers—cAMP, Ca2+, and cGMP—regulate electroneutral NaCl absorption. All

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SGK1: serum- andglucocorticoid-regulated kinase 1

SGLT1: Na+/glucosecotransporter 1

NHE-regulatoryfactor (NHERF): aPDZ-binding protein

PKC: proteinkinase C

Protein kinase A(PKA): a cAMP-dependent proteinkinase

cGK: cGMP-dependent proteinkinase

these second messengers inhibit NHE3 at theapical (brush border) membrane. The same sig-nals also regulate electrogenic Cl− and fluid se-cretion; i.e., increased cAMP, cGMP, or Ca2+

activates CFTR on the apical membrane. Thesesame signals [cAMP (69), Ca2+ (70), cGMP(71)] have no effect on glucose-coupled Na+

absorption. For example, glucocorticoids ac-tivate NHE3 via serum- and glucocorticoid-regulated kinase 1 (SGK1) (72, 73) as well asvia Na+/glucose cotransporter 1 (SGLT1) (72).Mineralocorticoids have weaker effects on elec-troneutral NaCl absorption by the small intes-tine (74, 75) while effectively activating colonicNa+ absorption by NHE3 [proximal colon (74)]and ENaC [distal colon (6)].

Regulation of NHE3 by cAMP, Ca2+,and cGMP

When the intestinal mucosa is stimulated byenterotoxins, neurotransmitters, or drugs, allof which increase intracellular cAMP (69, 76),Ca2+ (76–78), or cGMP (71), electroneutralNaCl absorption is inhibited, and electrogenicCl− secretion is activated. NHE3 is one ofthe main targets of these second messengers.These inhibitory mechanisms have beenanalyzed mainly in exogenous expressionsystems (mammalian culture) (for reviews,see References 10, 79, and 80) and knockoutmice (81, 82). This inhibition requires both sec-ond messenger–activated protein kinases andthe NHE-regulatory factor (NHERF) scaffoldproteins. Cultured cells and mice lackingNHERF(s) do not show second messenger–mediated inhibition of NHE3. NHERF(s)mediates interaction among the C-terminalPDZ-binding motif of NHE3, other mem-brane proteins, cytoskeleton, protein kinases,etc. cAMP-mediated inhibition of NHE3requires NHERF1 (NHERF), NHERF2(E3KARP) (83), and NHERF3 (PDZK1) (81).Similarly, Ca2+-mediated inhibition of NHE3requires NHERF2 (84, 85) and NHERF3(81), but not NHERF1. NHE3 inhibition bycGMP requires NHERF2, but not NHERF1or NHERF3 (81, 86). cAMP activates protein

kinase A (PKA)II, which anchors toNHERF1/2 via the cytoskeletal proteinezrin (also known as cytovillin or villin2), di-rectly phosphorylating multiple serine residuesin the cytoplasmic domain of NHE3 (83,87). Ca2+ induces membrane localization ofprotein kinase C (PKC)α, which interacts withNHERF2 and α-actinin 4 (84, 85, 88) andphosphorylates NHE3 (89). cGMP activatescGMP-dependent protein kinase II (cGKII orPKGII), which interacts with NHERF2, yet itis not known if cGKII directly phosphorylatesNHE3. In the renal proximal tubule (90)and in cultured Caco-2 cells (91), NHE3 ispresent in both apical membrane and clathrin-associated subapical endosomes, the latter ofwhich constitute the major endocytic pathway.cAMP (92) and Ca2+ (91) stimulate NHE3internalization in Caco-2 cells; this endocyticpathway requires synaptotagmin 1 and adaptorprotein 2 (AP2) (92). In vitro, NHE3 phos-phorylated by PKAα is still active (93). Thus,phosphorylation-mediated internalization ofNHE3 seems to be the dominant mechanismfor NHE3 inhibition by second messengers.

Conversely, activation of NHE3 occurs bydecreased intracellular pH (pHi) or increasedcellular metabolism (e.g., glucose transport anddecreased pHi) (94). Ezrin controls this NHE3activation by brush border translocation (95).

Regulation of NHE3 andNa+/K+-ATPase by Glucocorticoid,SGK1, and PI3K

In small intestine epithelial cells, glucocorti-coids activate electroneutral Na+ absorption(75), NKA (75), and SGLT1 (72, 96). The pro-moter of the rat Nhe3 gene has binding sites forglucocorticoid receptor (GR) and is activatedby glucocorticoids (97). NHE3 is also activatedby glucocorticoids via SGK1 phosphoryla-tion (73). Glucocorticoids activate SGK1 byinducing SGK1 gene expression (∼20 min);this activation occurs through stimulation ofPI3-kinase (PI3K) (6, 98, 99). PI3K synthe-sizes phosphatidylinositol-3,4,5-trisphosphate[PtdIns(3,4,5)P3] and PtdIns(3,4)P2 and


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CA: carbonicanhydrase

activates 3-phosphoinositide-dependent pro-tein kinase-1 (PDK1), which directly phospho-rylates SGK1 to activate it. NHE3 activationby SGK1 depends on the combined interactionof NHE3 and SGK1 with NHERF2 and thenphosphorylation at S663 of NHE3 by SGK1(73, 100). Analyses of Sgk1−/− mice demon-strated that glucocorticoids enhance intestinalNHE3 and SGLT1 protein abundance at thebrush border of wild-type mice but not that ofSgk1−/− mice (72).

In the proximal colon, mineralocorticoidsalso activate NHE3 (6, 74). There is a differen-tial effect of mineralocorticoids in small versuslarge intestine on NHE3 activation. This differ-ence arises from the differential expression andactivity of 11β-hydroxysteroid dehydrogenase(11β-HSD2), which is required for mineralo-corticoid function mediated by mineralocorti-coid receptors (101).

Regulation of Slc26a3/a6 bySecond Messengers

Studies of isolated intestinal mucosa demon-strated that Cl− influx is reduced and Cl− effluxis increased after stimulation by enterotoxins orneurotransmitters via increased cAMP concen-tration ([cAMP]) (69, 76), increased Ca2+ con-centration ([Ca2+]) (76–78), or increased cGMPconcentration ([cGMP]) (71). Thus, these sig-nals seem to inhibit Cl− absorption, perhaps bySlc26a3 and Slc26a6 activating Cl− secretionby CFTR (102). In contrast to NHE3 regula-tion, the inhibitory mechanism of Slc26a3 andSlc26a6 is poorly understood.

SLC26A3 has a C-terminal PDZ-bindingmotif, which can interact with the PDZ-2 do-main of NHERF2 (103) as well as the PDZ-2/-3domains of NHERF3 (104). In cultured cells,increased intracellular [Ca2+] (105, 106) and in-creased [cAMP] (106) inhibit exogenously ex-pressed Slc26a3. Interestingly, this Slc26a3 in-hibition does not occur after PMA (a PKCactivator), suggesting that PKC does not me-diate the inhibition of Cl−/HCO3

− exchange(105). cAMP and Ca2+ cause internalizationof Slc26a3 (similar to NHE3) in both cul-

tured cells and intestinal mucosa (106), sug-gesting that internalization is a major pathwayfor regulating Slc26a3 expression and thus itsapical Cl−/HCO3

− exchange. The interactionsof Slc26a6 and NHERFs have not been di-rectly demonstrated. Nevertheless, SLC26A6has no transport activity after removal of its C-terminal PDZ-binding motif (107, 108).

In contrast to the scenario with Slc26a3,PKC does regulate Slc26a6 activity (109). InHEK293 cells or in Xenopus oocytes, PKCseems to dissociate intracellular carbonic anhy-drase II (CAII) from its binding site on Slc26a6(109, 110). CAII catalyzes the reversible con-version between CO2 and HCO3

−; this pro-cess supplies the HCO3

− substrate to Slc26a6.Slc26a6 has a binding site for CAII, the dele-tion of which decreases Cl−/HCO3

− exchangeactivity (110). Mechanistically, PKC activationreduces the Slc26a6/CAII association, result-ing in reduced Slc26a6 activity in HEK293cells (110). In Xenopus oocytes, PKCδ medi-ates PMA-induced Slc26a6 inhibition and in-ternalization (109). CAII is also required for fullSlc26a3 activity in HEK293 cells, but direct in-teraction with CAII does not stimulate Slc26a3transport activity (111).

Cross-Regulation of NHE3, SLC26s,and CFTR

In the small intestine, absorption of NaCl andnutrients is mediated mainly by villus cells,whereas secretion of fluid containing Cl− andHCO3

− is mediated mainly by crypt cells.These findings are the synthesis of immuno-histochemical analyses demonstrating variabledistribution of ion and nutrition transportersand channels (51, 112). At the same time, it isalso believed that electroneutral NaCl absorp-tion and electrogenic Cl− secretion occur inthe same cells where transporters form macro-molecular complexes, which presumably allowsthe transporters to regulate and be regulated byeach other. How can this occur?

At the brush border, NHERFs scaffoldtransporters/channels (NHEs, Slc26s, andCFTR), cytoskeletal molecules, and kinases, as

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VIP: vasoactiveintestinal peptide

described above. Furthermore, several Slc26sassociate directly with CFTR. For Slc26a3and Slc26a6, phosphorylation of the CFTRR-region by PKA mediates this interaction,apparently allowing interaction with theSlc26-STAS domain (27, 102). When the twoproteins are exogenously coexpressed, cAMP-mediated interaction activates the Cl−/HCO3

−

and Cl−/OH− exchange activities of SLC26sand the overall open probability of CFTR (27,102). This model is developed for the fluidsecretion of pancreatic duct cells, but a similarsystem may be present in the intestinal epithe-lium. Conversely, when Slc26a9-STAS andR-CFTR interact, Slc26a9 function is inhib-ited, and this interaction-mediated inhibitiondoes not require phosphorylation (55).

Studies using jejunal mucosa of CFTR−/−

mice indicated that such mice lack not onlycAMP-mediated Cl− secretory activity but alsocAMP-mediated inhibition of electroneutralNaCl absorption (113). These data suggest invivo involvement of CFTR in the regulation ofNHEs and Slc26s (4, 114). CFTR activationreduces the cell volume in the villus epithe-lium and induces cell shrinkage. Hypertonicmedium (causing cell shrinkage) also inhibitselectroneutral NaCl absorption (115). Incontrast, inhibition of duodenal NHEs bycertain inhibitors can stimulate CFTR andHCO3

− secretion (112, 116). Cultured cellscoexpressing NHE3, CFTR, and NHERF2show inhibition of PKA-mediated CFTRactivity, which depends on the interaction ofNHE3 and NHERF2 (117).

Coexpression of Slc26a3 and NHE (NHE2or NHE3) results in transport activation (106).In this system, anion inhibitors (e.g., DIDSand niflumic acid) block not only Slc26a3 activ-ity but also NHE activity. Likewise, dimethyl-amiloride (an NHE inhibitor) blocks NHE2/3activity as well as Slc26a3 activity.

Increased cellular cAMP is restored to basallevels by (a) hydrolysis of cAMP to 5′-AMPby phosphodiesterases (PDEs) or (b) cAMP ef-flux by MRP4 (ABCC4, an ABC transporter).MRP4 physically associates with CFTR viaNHERF3 and thereby inhibits CFTR (118).

MRP4 may also control NHE3 activity by reg-ulating local intracellular [cAMP].

REGULATION OF EPITHELIALNaCl ABSORPTION

Epithelial absorption and secretion in the smallintestine are regulated by the endocrine system,the autonomic nerve system, and the immunesystem (Figure 2). The intestine has many en-teric nerves that form interconnected networkswithin the intestinal wall and project directlyto the epithelium. Thus, both direct regulationand enteric nerve–mediated regulation of ep-ithelial cell transport are operative.

Enteric nerves are composed of the myen-teric plexus and the submucosal plexus, whichcan function even when disconnected from thecentral nerve system (119). Both enteric nervesand epithelial cells are regulated by sympatheticnerves (proabsorptive effect), parasympatheticnerves (secretory/antiabsorptive effect), the en-docrine system and paracrine system (pro- andantiabsorptive effect), and immune system (se-cretory effect) (120–123). Although the mecha-nisms of enteric nerve–mediated regulation arenot fully understood, the end result is mediatedpredominantly by norepinephrine (proabsorp-tive effect), somatostatin (proabsorptive effect),acetylcholine (secretory effect), and vasoactiveintestinal peptide (VIP) (secretory effect).

Secretory Regulation byNeuroendocrine Systems(Acetylcholine, Vasoactive IntestinalPeptide, Substance P, 5-HT)

Parasympathetic (cholinergic) neurons, cholin-ergic secretomotor neurons, and VIP secreto-motor neurons mediate the secretory (antiab-sorptive) neural effect. Acetylcholine and VIPinhibit electroneutral NaCl absorption and in-duce electrogenic Cl− secretion in the smallintestine epithelium. M3 muscarinic receptors(which increase cellular [Ca2+]) and VIP recep-tors (which increase [cAMP]) on epithelial cellsmediate this secretory effect (124).


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–

– +

Lumen

EndocrineImmune

ACh

+Histamine

IFN-γ

GC

NH

E3

NHE3

Mast cell

Th1+ Histamine

NE

GiGq

VIP

Gs

PGE2

Gs

Adrenal cortex

GN, UGN

nhe3

SST

Gi

D cell

EC cell

SGK1PKAα

PKCα

cGKII

cGMP

Ca2+cAMP

+

5-HT

NPY

Gi

NPY

S cell

PYY

Enteric nerve

NE

AChVIP

FibroblastAII5-HT

SPANP

++NESSTEK

PGE25-HT

Figure 2Regulation of NHE3 by the endocrine system, the nervous system, and the immune system. Absorptive (antisecretory; red ) andsecretory (antiabsorptive; blue) signals are indicated. Abbreviations: 5-HT, 5-OH-tryptamine or serotonin; AII, angiotensin II; ACh,acetylcholine or cholinergic neuron; ANP, atrial natriuretic peptide; cGKII, cGMP-dependent protein kinase II; EC, enterochromaffincell; EK, enkephalin; GC, glucocorticoid; GN, guanylin; IFN-γ, interferon-γ; NE, norepinephrine or norepinephrinergic neuron;NHE3, Na+/K+ exchanger 3; NPY, neuropeptide Y; PGE2, prostaglandin E2; PKAα, cAMP-dependent protein kinase α; PKCα,protein kinase Cα; PYY, peptide YY; SGK1, serum- and glucocorticoid-regulated protein kinase 1; SP, substance P; SST,somatostatin; Th1, T helper cell type 1; VIP, vasoactive intestinal peptide or VIPergic neuron; UGN, uroguanylin.

5-HT:5-OH-tryptamine;also known asserotonin

Substance P is an 11-amino-acid peptide,and its receptor is neurokinin 1 receptor (NK1).Substance P is found in myenteric and sub-mucosal neurons and has a secretory effect(125). A voltage-gated Na+ channel blocker,tetrodotoxin, largely inhibits this secretory ef-fect, suggesting that secretomotor neurons me-diate the effect. Both cholinergic and non-cholinergic secretomotor neurons are involved;NK1 mediates the cholinergic effect (125, 126).

Serotonin [also known as 5-OH-tryptamine(5-HT)] is secreted from both the enteric

nerves in the myenteric plexus and ente-rochromaffin (EC) cells (127, 128), whichsense luminal molecules (129). The antiab-sorptive and prosecretory effect of 5-HTis mediated predominantly by cholinergicand VIP secretomotor neurons. In Caco-2cells, the 5-HT4 receptor mediates PKCα

activation, inhibition of NHE activity, andreduction of NHE3 transcription (130). 5-HTalso modifies the brush border architec-ture, which in turn reduces NHE3 function(131).

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IPSP: inhibitorypostsynaptic potential

Atrial natriureticpeptide (ANP): ANPand its related peptides(BNP and CNP) arepeptides that decreaseblood pressure andincrease natriuresis

Absorptive Regulation byNeuroendocrine Systems(Catecholamines, Somatostatin,Opioids)Norepinephrine (secreted by the adrenal glandor sympathetic nerve termini) and other cat-echolamines increase electroneutral NaCl ab-sorption and decrease electrogenic Cl− secre-tion by intestinal mucosa. Catecholamines actat the α2-adrenergic receptor (132) on ep-ithelial cells (133). The α2-adrenergic recep-tor couples with inhibitory G proteins Gi2 andGi3 (134), which antagonize cAMP production.Additionally, second messenger–independentinhibition of Cl− secretion by Gi has beensuggested for colonic epithelium (135). Cate-cholamines (through the α2-adrenergic recep-tor) also elicit noradrenergic inhibitory postsy-naptic potentials (IPSPs) of VIP secretomotorneurons in the submucosal plexus (120, 136).

Somatostatin is a 14- or 28-amino-acid pep-tide secreted by extrinsic and intrinsic neu-rons of the intestinal myenteric and submucosalplexus, as well as by endocrine D cells in theepithelium throughout the gut (137, 138). So-matostatin analogs activate electroneutral NaClabsorption in the intestine. Secretory diarrheacaused by VIP-producing (Verner-Morrisonsyndrome) or serotonin-producing (carcinoidsyndrome) tumors demonstrates an inhibitoryeffect of somatostatin (139). Somatostatin re-ceptors (SSTR1 and SSTR3) are expressedin the epithelium as well as in enteric neu-rons of the submucosal and myenteric plexuses(140). SSTR2 is expressed in enteric neuronsbut not in epithelial cells (141). Somatostatin(via SSTR1/SSTR2) also elicits nonadrenergicIPSPs of VIP secretomotor neurons (120, 136).

Opioids (morphine, enkephalin) cause smallintestine absorption (142, 143). The δ-opioidreceptor is found in submucosal and myentericneurons and mediates the inhibition of VIP se-cretomotor neurons by enkephalin. Prolongedmorphine use results in astriction by stimulat-ing NaCl absorption. Accordingly, enkephali-nase is a drug target for diarrhea.

Neuropeptide Y is a 36-amino-acid pep-tide and is present in both myenteric and

submucosal neurons (144, 145). In the sub-mucosal plexus, neuropeptide Y is found incholinergic and noncholinergic secretomotorneurons. Neuropeptide Y inhibits VIP-inducedcAMP synthesis and Cl− secretion, as well asprostaglandin-elicited Cl− secretion. The ab-sorptive (antisecretory) effect of neuropeptide Yis mediated by norepinephrine (α2-adrenergicreceptors) in the ileum (146), whereas neu-ropeptide Y–elicited absorption is mediated viaY1 receptors in the human colonic epithelium(144).

Regulation by the Paracrine Systemand the Endocrine System

Guanylin and uroguanylin are 15–16-amino-acid peptides and are present in serotonin-positive EC cells of the small intestine (147).Luminal peptide secretion, stimulated by saltingestion, elicits an increase in intracellularcGMP in epithelial cells via the apical recep-tor for guanylate cyclase C (GC-C) (148, 149).

Peptide YY (PYY) is a 36-amino-acid guthormone that is released from endocrine L cellsof the ileal mucosa following a meal. PYY sharessequence homologies and therefore also a re-ceptor with NPY. Like NPY, PYY is absorptive(antisecretory) in the small intestine (145).

As mentioned above, glucocorticoids acti-vate electroneutral NaCl absorption as well asnutrient-coupled Na+ absorption in the smallintestine. Mineralocorticoids play a significantrole in the stimulation of colonic Na+ absorp-tion but have little effect on the regulation ofsmall intestinal NaCl absorption. Low dosesof angiotensin II (which acts at the AT2 re-ceptor) stimulate intestinal electroneutral NaClabsorption (150) indirectly via norepinephrinesecretion by sympathetic nerves (151, 152). An-giotensin II also antagonizes the secretory effectof VIP (153).

Atrial natriuretic peptide (ANP) and itsrelated peptides [B-type natriuretic peptide(BNP) and C-type natriuretic peptide (CNP)]are a family of peptides that reduce bloodpressure and induce natriuresis. Natriureticpeptides reduce intestinal NaCl and water


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absorption and increase intestinal fluid content(154–157). This natriuretic action affects the je-junum but not the ileum in dog (155). ANPstimulates cGMP synthesis in cultured rat ilealcells via the guanylate cyclase A receptor (157,158). The antiabsorptive effect of natriureticpeptide is inhibited by tetrodotoxin and anantagonist of 5-HT receptor, suggesting themediation of enteric nerves (159). How-ever, the intestinal role of natriuretic pep-tides is still controversial, and detailed regu-latory mechanisms have not been completelyclarified.

Immune Regulation of Secretion

Mediators of enteric immune system also havesecretory (antiabsorptive) effects on intestinalepithelium (160). Prostaglandin E2 (PGE2) in-creases electrogenic Cl− secretion and inhibitselectroneutral NaCl absorption (161). Becauseatropine or tetrodotoxin does not inhibit theseeffects (162), PGE2 may directly induce intra-cellular cAMP to be activated by its receptorspresent in the plasma membrane of intestinalepithelium (163). PGE2 is secreted by acti-vated fibroblasts (164), and indomethacin in-hibits such secretion (162).

Histamine, secreted by activated mast cells,elicits a short-circuit current in intestinal ep-ithelium. Atropine or tetrodotoxin blocks thiscurrent in rat jejunum (162), suggesting themediation of cholinergic enteric nerves. In thecolon, the histamine H1 receptor (which in-creases intracellular [Ca2+]) directly mediatessecretion by the epithelial cells (165). Activatedmast cells secrete 5-HT (162, 165), which canalso cause epithelial secretion.

T cell activation inhibits intestinal Na+

absorption, increases Cl− secretion, increasesintestinal permeability, and causes diar-rhea. Tumor necrosis factor-α (TNF-α)and interferon-γ (IFN-γ) mediate these Tcell–elicited physiological changes. In mousejejunum, TNF-α inhibits epithelial NHE3(apically) and NKA (basolaterally) (166, 167),thereby decreasing transepithelial NaCl ab-sorption. IFN-γ reduces the transcriptionalactivity of the nhe3 gene in rat ileum and colonand in Caco-2/bbe cells (168), decreasingthe number of NHE3 transporters and thusdecreasing NaCl absorption. Finally, IFN-γalso reduces Slc26a3 and Slc26a6 expressionin Caco-2 cells (169, 170), likely decreasingCl− uptake. Again, the net result is decreasedintestinal NaCl absorption.

SUMMARY POINTS

1. Electroneutral NaCl absorption by the small intestine is mediated by NHE2, NHE3,Slc26a3, Slc26a6, and Slc26a9 at the apical membrane and by NKA at the basolateralmembrane of the small intestine. Physiological analyses of knockout mice demonstratethat facilitating electroneutral NaCl absorption is the dominant function of NHE3,Slc26a3, and Slc26a6 in the intestine.

2. Intracellular pH and intracellular [HCO3−] control intestinal NaCl absorption directly

(with H+ and HCO3− as substrates) and indirectly (through pH dependency of trans-

porters and metabolic HCO3− production).

3. Direct interaction or NHERF-mediated interaction among NHE3, Slc26s, CFTR, andprotein kinases regulates transport activities. Electroneutral NaCl absorption and elec-trogenic Cl− secretion are oppositely controlled by intracellular cAMP, Ca2+, and cGMP.

4. The endocrine system, autonomic nerve system, and immune system can regulate ep-ithelial NaCl transport function directly or indirectly via the enteric nervous system andtransporter gene expression.

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FUTURE ISSUES

1. Does control of the basolateral transporters and channels in the intestine involve merelya few key proteins, or is such control more complicated?

2. How does diet affect intestinal NaCl absorption? For example, can abundance of apicaltransport substrates (e.g., sulfate, oxalate) control efficacy of NaCl absorption?

3. What is the clinical effect of intestinal resection on NaCl absorption?

4. Does systemic acid-base status affect intestinal NaCl absorption?

DISCLOSURE STATEMENT

The authors are not aware of any affiliations, memberships, funding, or financial holdings thatmight be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS

We thank the members of the Romero (Case Western Reserve University and the Mayo Clinic) andHirose (Tokyo Institute of Technology) groups for discussions and contribution to the originalresearch discussed here. We apologize to colleagues whose work we were not able to cite dueto space constraints. A.K. was supported by Ministry of Education, Culture, Sport, Science, andTechnology of Japan (MEXT) Grants-in-Aid for Scientific Research 14104002, 18059010, and21770077 and by the Twenty-First Century and Global Center of Excellence Program of MEXT.M.F.R. is supported by NIH (DK056218, EY017732, P50-DK083007) and by the Mayo ClinicCenter for Cell Signaling in Gastroenterology (P30-DK084567).

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PH73-FrontMatter ARI 14 January 2011 10:0

Annual Review ofPhysiology

Volume 73, 2011Contents

PERSPECTIVES, David Julius, Editor

A Long Affair with Renal TubulesGerhard H. Giebisch � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 1

CARDIOVASCULAR PHYSIOLOGY, Jeffrey Robbins, Section Editor

Heart Valve Structure and Function in Development and DiseaseRobert B. Hinton and Katherine E. Yutzey � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �29

Myocardial Remodeling: Cellular and Extracellular Events and TargetsJennifer A. Dixon and Francis G. Spinale � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �47

ECOLOGICAL, EVOLUTIONARY, AND COMPARATIVE PHYSIOLOGY,Martin E. Feder, Section Editor

Ecological Physiology of Diet and Digestive SystemsWilliam H. Karasov, Carlos Martınez del Rio, and Enrique Caviedes-Vidal � � � � � � � � � � � � �69

Effects of Oxygen on Growth and Size: Synthesis of Molecular,Organismal, and Evolutionary Studies with Drosophila melanogasterJon F. Harrison and Gabriel G. Haddad � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �95

LEA Proteins During Water Stress: Not Just for Plants AnymoreSteven C. Hand, Michael A. Menze, Mehmet Toner, Leaf Boswell,

and Daniel Moore � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 115

ENDOCRINOLOGY, Holly A. Ingraham, Section Editor

Endocrine Disruptors: From Endocrine to Metabolic DisruptionCristina Casals-Casas and Beatrice Desvergne � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 135

Endometriosis: The Role of NeuroangiogenesisAlbert Asante and Robert N. Taylor � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 163

Zebrafish in Endocrine Systems: Recent Advances and Implications forHuman DiseaseHeiko Lohr and Matthias Hammerschmidt � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 183

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GASTROINTESTINAL PHYSIOLOGY, James M. Anderson, Section Editor

Mesenchymal Cells of the Intestinal Lamina PropriaD.W. Powell, I.V. Pinchuk, J.I. Saada, Xin Chen, and R.C. Mifflin � � � � � � � � � � � � � � � � � � � � 213

Niemann-Pick C1-Like 1 (NPC1L1) Protein in Intestinal and HepaticCholesterol TransportLin Jia, Jenna L. Betters, and Liqing Yu � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 239

Regulation of Electroneutral NaCl Absorption by the Small IntestineAkira Kato and Michael F. Romero � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 261

Tight Junction Pore and Leak Pathways: A Dynamic DuoLe Shen, Christopher R. Weber, David R. Raleigh, Dan Yu, and Jerrold R. Turner � � � 283

NEUROPHYSIOLOGY, Roger Nicoll, Section Editor

How the Genetics of Deafness Illuminates Auditory PhysiologyGuy P. Richardson, Jacques Boutet de Monvel, and Christine Petit � � � � � � � � � � � � � � � � � � � � � � 311

RENAL AND ELECTROLYTE PHYSIOLOGY, Gerhard H. Giebisch, Section Editor

Mechanisms Underlying Rapid Aldosterone Effects in the KidneyWarren Thomas and Brian J. Harvey � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 335

Regulation of Renal NaCl Transport by Nitric Oxide, Endothelin,and ATP: Clinical ImplicationsJeffrey L. Garvin, Marcela Herrera, and Pablo A. Ortiz � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 359

Renin Release: Sites, Mechanisms, and ControlArmin Kurtz � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 377

Terminal Differentiation in Epithelia: The Role of Integrinsin Hensin PolymerizationQais Al-Awqati � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 401

RESPIRATORY PHYSIOLOGY, Richard C. Boucher, Jr., Section Editor

Epithelial-Mesenchymal Interactions in Pulmonary FibrosisHarold A. Chapman � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 413

Interaction of Cigarette Exposure and Airway EpithelialCell Gene ExpressionJerome S. Brody and Katrina Steiling � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 437

The Lung: The Natural Boundary Between Nature and NurtureMax A. Seibold and David A. Schwartz � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 457

viii Contents

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Role of Chitin and Chitinase/Chitinase-Like Proteins in Inflammation,Tissue Remodeling, and InjuryChun Geun Lee, Carla A. Da Silva, Charles S. Dela Cruz, Farida Ahangari,

Bing Ma, Min-Jong Kang, Chuan-Hua He, Seyedtaghi Takyar,and Jack A. Elias � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 479

SPECIAL TOPIC, THROMBOSIS, Charles T. Esmon, Special Topic Editor

The Link Between Vascular Features and ThrombosisCharles T. Esmon and Naomi L. Esmon � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 503

Role of Tissue Factor in Venous ThrombosisDavid A. Manly, Jeremiah Boles, and Nigel Mackman � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 515

Venous Valvular Stasis–Associated Hypoxia and Thrombosis: What Isthe Link?Edwin G. Bovill and Albert van der Vliet � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 527

Indexes

Cumulative Index of Contributing Authors, Volumes 69–73 � � � � � � � � � � � � � � � � � � � � � � � � � � � 547

Cumulative Index of Chapter Titles, Volumes 69–73 � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 550

Errata

An online log of corrections to Annual Review of Physiology articles may be found athttp://physiol.annualreviews.org/errata.shtml

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