Physiology Exam 1 Lecture Objectives

7/25/2019 Physiology Exam 1 Lecture Objectives

1/40

Physiology Exam 1 Lecture Objectives

Membranes:

1. Role of membrane in maintaining composition of intracellular fluid (Homoeostasis)

a.

Does so by compartmentalizationb. Bilayer is impermeable to hydrophilic substances (dissolves well in water)i. Permeable to gases and lipid soluble molecules

ii. All else requires special transporteriii. Thus membrane is semi-permeable

c. K+ is major ion in cytoplasmd. Na2+ is major ion in extracellular fluid

2. Membranes main functionsa. Physical boundary of cell and intracellular organelles

b. Compartmentalization (separation)c. Transport

i.

Physical matterii. Information (communication)

1. Across Membrane (Signal Transduction) - Intracellular2. Along Membrane (Propagation)Intercellular

a. Excitability

3. Main function of the main constituents

a. Glycocalyx (cell coat): carb of glycolipid and glycoproteinsi. Protection

ii. Lubricationiii. Cell/cell recognition (ex: blood groups_

b. Membrane Proper: lipids and proteins

c.

Cell Cortex (part of cytoskeleton): proteinsi. Cortical actin

ii. Integrity, flexibility, control of membrane proteins

iii. Spectrin/actin cortex keeps integrity of RBC

4. Composition of membrane lipids:

a. Phospholipids:i. Form bilayer due to phospholipid polarity

ii. Move freely within plane of bilayer (lateral movement) fluidity


2/40

iii. Individual phospholipids can rotate (rotational movement)iv. Bilayer held by hydrophobic interactions no transverse movement

b. Cholesterol:i. 50% of lipids in membrane

ii. Enhances fluidity by preventing phospholipids from packing closely

iii.

Hydrophobic + Hydrophilic areas like phospholipid bilayeriv. High temp environment more cholesterol in membranev. Enhances impermeability by filling gaps in phospholipids

vi. Reduces cells ability to lyse by making it more flexiblec. Glycolipids:

i. Only in plasma membraneii. Sugar chain (15 polar units) covalently bonded to phospholipid

iii. Always towards outside of cell membraneiv. Cell recognitions

v.

Cell receptor

vi. Control/regulates function of membrane proteins

d.

Sphingolipidsi.

Signaling molecule

ii.

Makes myeliniii. Based on sphingosine + fatty acid

iv. Has double bond near polar amine end of sphingosinev. Hydrophobic + Hydrophilic areas resembles phospholipids

5. Role of hydrophilic and hydrophobic interactions

a. Hydrophobic Molecules: stick together in water to cause less disruption

i.

Ex: lipids form droplets in cell cytoplasmb. Hydrophilic Molecules: surrounded by shell of water

6. Role of hydrophilic and hydrophobic interactions among molecules in the self-assembly

of membrane bilayera. Amphiphilicity: hydrophilic head and hydrophobic tail form micelles in water

b. Bilayer formed by amphipathic lipidsi. Core is very hydrophobic water cannot pass through

ii. Held together by hydrophobic interactions


3/40

Diffusion and Osmolarity:

1. Various expressions of concentration:

2. Molar expression of concentration:

M =

1 mole = 6 1 023molecules (Avogadros number)

3. Factors that determine direction of diffusion:a. Concentration of particles

b. Barrier has to be permeable


4/40

4. Main factors that determine Flux and express them quantitatively in Ficks law:

a. Flux: rate of diffusion (

)

b. Factors that determine flux:i. Membrane Permeability

ii.

Size of particle (heaver = slower)c. Ficks Law: flux is proportional to concentration difference

i. Higher difference = higher flux

5. Know membrane and solute properties that determine permeability for diffusion:

a. Permeability:i. Proportionality constant between flux and concentration gradient

ii. Differs for different membrane and substancesb. Higher Permeability:

i. Membranes: higher area and thinnessii. Solutes: uncharged, small, and large partition coefficient

6.

Distinguish solutes that permeate through bilayer and those that permeate throughtransport proteins:

a. Solutes through Bilayer:

i. Gasesii. Small, non-ionic

iii. Fat-solubleiv. Substances w/ high partition coefficient (fat soluble)

1. Codeine2. Xylocaine/Novocain

b. Solutes through Transport Proteins:i. Large, polar

7. Apply above rules to diffusion of water (osmosis)

a. Can pass through water-permeable membraneb. Occurs through aquaporins

c. Water from high to low concentrationd. Water stops moving when fluxes from both sides are equal

e. Can be stopped by applying hydrostatic pressure


5/40

8. Osmolarity and osmotic pressure:a. Osmolarity: total concentration of particles of solutes regardless of chemical nature

i. ONLY number of impermeable particlesb. Osmotic Pressure: caused by solute molecules

i. Use vant Hoffs Law:

ii. Equal to pressure of solutesiii. Osmotic Pressure increases as solute concentration increases

1. Ex: 1 M CaCl2is higher than 1 M KCliv. No hydrostatic pressure difference = sum of osmotic pressures off solutes is 0


6/40

Ions: Voltages

1. Measurement of membrane potentiala. Use voltmeter to measure voltage difference Vi-Ve

b. Neurons: -70mV

c.

Skeletal Muscles: -90mV2. Requirements for existence of electrical forcesa. Whenever excess charge of one sign is in one region

b. Opposite charges attract, remaining charged particles allow for electrical potentialdifference

3. Definition of electrical potential and electrical potential differencea. Electrical Potential: potential energy of the unit of charge

b. Electrical Potential Difference: excess charges cause differencei. Has ability to do work

4. Capacitancea. Proportionality constant between charge and membrane potential

b.

Capacitance = Charge/Potentialc.

Thicker membrane = more work = more potential = less capacitance

i.

Key for why nerves are myelinated

5. Electrochemical equilibrium for one ion

a. Assume K+ and Cl- on both sides of membrane only permeable to K+b. There is more K+ on left side thus due to chemical gradient it will diffuse to the right

until in chemical equilibriumc. This buildup causes an electrical gradient with + signs built up on the right of the

membrane andsigns on the leftd. Due to the attraction of opposite charges, the K+ will want to go back to the left side

of the membrane and will do so. This will then cause a shift in the concentrationgradient and cause K+ to want to go back to the right.

e.

Both an electrical and chemical gradient will oppose one another causing anelectrochemical equilibrium

f. *Water only depends on concentration gradient not membrane potential

6. Application of Nernst equation to specific examples with the 4 main ions

a. Only Cl- is at equilibrium b/c it is at -70mV


7/40

7. Application of Nernsts equation to nerve cell at rest, difference between resting

potential and equilibrium potential of ions

a. Equilibrium Potential: defined per ion (property of ion not membrane)b. Resting Potential: is for membrane and takes into account all ions involved

c. If membrane only permeable to K+, Ek= Vmd. Resting potential always more positive than Ekbecause membrane is also permeable

to Na+and Cl-e. Each permeable ion drives membrane potential towards its equilibrium potential

i. Ions with greatest permeability will make greatest contribution to restingmembrane potential

ii. At rest, nerve membrane is more permeable to K+ than to Na+

8. Electric potential difference generated when multiple permeant ions are present at

unequal concentrations. GHK equation (Goldman-Hodgkin-Katz)

9. Electrochemical potential difference (EPD)a. Difference between actual transmembrane potential (Vm) and equilibrium potential of

ioni. Ex: Ek = -90, Vm = -70 -70 - -90 = +20 (EPD)K+ will move out

b. Cl- acts as stabilizer for membrane potential since Ecl= -70 just like Vm


8/40

Transporters: Pumps and Carriers:

1. The crucial role of the Na+ pump in maintaining resting potentiala. Na/K pump maintains concentration differences that originate the resting potential

by working against the passive fluxes of Na and K

b.

2 K in / 3 Na out for each ATP hydrolyzedc. Causes accumulation of extracellular positive charge (electrogenic)

2. Classification of transport mechanisms:(energy consumption + structure)a. Passive:

i. Simple (channel protein) substances move right through membraneii. Facilitated (transporter protein)

iii. Driven ONLY by electrochemical potential difference (EPD)b. Active (transporter protein)

3. Simple diffusion vs. carrier-facilitated diffusiona. Diffusion can be either simple or carrier mediated (facilitated)

b. Facilitated uses channels or carriersc. Look at chart above

d. 3 Main differences:

i.

Saturationii.

Specificityiii. Competition

e. Facilitated diffusion only has certain amount of binding sites so asconcentration increases the flux will not be linear as in Ficks law,

but it will level off


9/40

4. Examples of single carriers with a single substratea. Primary active transport

5. Main pumps (primary active carriers). Stoichiometry of plasmalemmal Na-K pump

a. Primary active carriers:

i.

Protein molecule (pump) associate (couple) the transfer of solute acrossmembrane with use of ATPii. Ex:

1. Na/K pump in plasma membrane2. Ca pump in endoplasmic reticulum

3. H+ pump for HCl secretion in stomach

6. Coupled carriers: cotransporters and counter-transporters:a. Transfers solute without ATP, but uses energy stored in electrochemical potential

difference

b. Both (secondary active transporters) always use Na

c.

Exchanger = Counter-transporter (bubblegum machine)i.

Na-Ca exchanger 3 Na goes inside with gradient, 1 Ca outside against

d.

Cotransporter:i. Na/glucose Na goes along gradient, Glucose against

7. General organization of transporting epithelia:

a. Occurs in exocrine glands and lumen of absorptive organsb. Single layer of cells does the transport

c. Main thing: polarityi. Epithelia has 2 sides apical/lumenal and basolateral (interstitial)

d. Apical (lumen) and basolateral (blood) sides are different in composition,meaning transport molecules

i.

Difference maintained by tight junctionse. Basolateral: rich in Na/K pumps maintains electrochemical gradient for Na

8. Absorption of glucose in small intestine

a. Glucose concentration must be high for it to go into bloodb. Glucose and Na move together on apical side

c. Glucose goes into celld. Interstitial side has glucose carrier to move glucose down gradient

9. Reabsorption of Na+ and fluid in intestine and absorptive epithelia

a. Na moves from apical to interstitial side water will followi.

Na goes through epithelial Na channel (EnaC or Amiloride-sensitive

channel)ii. Channels of these increased by aldosterone

iii. Channels different than voltage-gatedb. At basolateral side, there is Na-K pump

c. 3 Na out, 2 K in


10/40

10.Secretion of Cl- and fluid in secretory epitheliaa. Ex: sweat gland

b. CFTR is Cl- channel on apical endi. In cystic fibrosis: channel doesnt work thick mucus secreted

c. Cl- moves from interstitial to apical

d.

Basolateral end:i. Cotransporter Na, K, 2Cl together into cell from interstitial ende. Apical end:

i. Na and H2O go down gradients in through tight junction both secretedat apical end

ii. Cl secreted through CFTR


11/40

Transporters: Channels

1. Main Characteristics of ion channels: selectivity, conductance, gating

a. Total current through 1 type of channel is sum of single channel currentsb. Amplitude of ionic current independent of opening/closing kinetics of channel

c.

Open Probability in formula is a kinetic characteristicd. Current depends on voltage and ion concentration

e. Driving force of ions through open channel = EPDi. High driving force = lots of current

ii. Driving force at 0 = equilibriumf. Condunctance high = large current = steeper curve

g. Pois function of voltage gates open/close depending on voltage

2. Concepts of sensors, gates, selectivity filtera. Gates

i. Channels are either on or off, no halfwayii. Gates represent movement of proteins that permit flux

iii. Movement of gates are too fast to observeb.

Gating Mechanisms:

i. Open:1. Contribute to resting potential

2. Always open3. Usually K+

ii. Voltage gated:1. Responds to change in membrane potential


12/40

iii. Extracellular Ligand-Gated:1. Responds to extracellular neurotransmitters (AcH, glycine)

iv. Intracellular Ligand-Gated1. Responds to intracellular signal transduction events

2. Ca channels that sense ATP

3.

Regulation of insulin

Ca channels close when sugar highv. Mechano-sensitive:1. responds to mechanical stress

2. membrane surface tensionc. Selectivity Filter:

i. Does not depend on flux or gating mechanisms (open probability)ii. Responsible for how much and what ions move in after gate opens

iii. Can determine by looking at graph1. K+ has eq. potential at -90mV (Case 1)

2.

Na+ at +60 (Case 3)

3. Not selective (Case 2)

d. Sensors:i. When depolarized, inside is charged more positively

ii.

Gating particle (positively charged) moves away from positive interior andpulls the positive ions through the gate

3. Main properties of voltage-gated Na and K channels that underlie action potential

a. K Channel:i. Activation gate is slow while Na activation fast, inactivation slow

ii. Activation gate is so slow that inactivation gate can be disregarded sinceactivation gate is the limiting factor

b. Na Channel:i. Inactivation on inside and activation gate inside channel

ii. At rest:

1.

Activation gate closed2. Inactivation gate open

iii. First 2-5 ms. of Depolarization:

1. Both gates openiv. Prolonged Depolarization:

1.

Activation gate open2. Inactivation gate closed

v. Back to negative membrane potential:


13/40

1. Both gates closed (inactivation gate lags)vi. After recovery back to resting membrane potential:

1. Activation gate closed2. Inactivation gate open

4.

Stead-state activation and inactivation gates in voltage-gated Na channelsa. Inactivation Curve:i. Neg. voltage = inactivation gate open

ii. Pos. voltage = closedb. Activation Curve:

i. Neg. voltage = closedii. Pos. voltage = open

c. Both gates open at same time is small fraction of time

5. Molecular topology of voltage-gated channels and determinants of the voltage sensors,

gates, and the selectivity filter in voltage-gated K channels

a. Voltage-Gated Channelsi. Created by 1 polypeptide

ii.

3-4 subunitsiii. Pore-forming subunit = 1

iv. Each subunit has domain (1-6 parts + loop pattern)v. Loop is between 5 and 6 is selectivity filter

vi. 4 = voltage sensor, gating portionb. In potassium channels it is very similar

i. ONLY 1 domain, tetramerii. Same complexity as Na channel, but smaller

iii. 1-6 parts are -helicesiv. Part 4:

1. Lysine (K) and Arginine (R) come every 2-

3 amino acids, 5-7 per helixc. KcsA K+ Channel:

i. Two transmembrane segments with carbonyl

oxygensii. Side chains pulled apart to give exact match for K+

1. Highly selective2. Highly conductive


14/40

6. Examples of channelopatheis diseases due to alterations of channels

a. Results from one amino acid alteration (point mutation)b. Paramyotonia congenita

c. Hyperkalemic Periodic Paralysis

d.

Potassium Aggravated Myotoniae. All result in stiffness, followed by weakness of muscle7. Na channel myotonias:

a. Transmitted as dominant traitb. Caused by a point mutation in gene

c. Associated with change in function of Na channel inactivation gated. Activation gate normal

e. Stiffness followed by weaknessf. Multiple response to single stimulus

g.

Worsened by exercise, cooling, potassium rich foods

8. Stabilizing role of Cl channels and causes of myotonia congenital

a.

Cl channel myotonias aka myotonia congenital is associated with reduced numberof functional Cl channels in muscle membrane

b.

At rest Cl ions are at equilibrium no passive fluxc. Cl ions exerts negative feedback on membrane potential, making it stable

i. Will not allow membrane to respond to action potential to smallperturbations of resting potential

d. In myotonia, Cl ionas are greatly reduced membrane less stablee. Only affects muscles NOT heart

f. Treatment:i. Exercise

ii. Drugs that inhibit Na+ channels (quinine, phenytoine)


15/40

Signal Transduction

1. Distinguish between endocrine, neurocrine, paracrine, and autocrine mechanisms of

extracellular signaling based on site of hormone release and pathway to target tissue:

a. Neurocine:

i.

Like telephone wire

direct = fastii. Problem is with many cells = hard to coordinateiii. Uses neurons

iv. Synaptic signaling with neurotransmitters at synaptic cleftv. Signals: AcH, glutamate

b. Endocrine:i. Chemical signals

ii. Endocrine cells release hormones into blood to target cells with correctreceptor

iii.

Signals: insulin, epinephrinec. Paracrine: (local)

i.

Nearby cells talking to each other (same cell in same tissue)ii.

Signals: cytokines, histamines, prostaglandins

d.

Autocrine: (local)i. Releases messages that that it reads itself

ii. immune signalingiii. Signals: cytokines, histamines, prostaglandins

e. Juxtacrine:i. Signaling chemical does not leave cell surface

ii. Signals by plasma membrane-attached proteins

2. Concepts of cell surface hormone receptors and signal transduction through second

messengers. Explain how/why these differ for cell-permeant hormones (steroids)

a.

Cell surface hormone receptors:i. On plasma membrane of cell surface and receives hormone

ii. Signal relayed to intracellular targets by signal transductioniii. Long term effects alterations in gene expression

iv. Short term effects altering protein function, protein phosphorylationb. Cell-permeant hormones:

i. Lipophilic so it can pass through membraneii. Goes straight to nucleus to regulate gene

c. Both ways can change cell behavior:i. Altering protein function (intracellular signaling pathway)

ii. Altering protein synthesis (gene expression)

3. Describe basic signaling mechanisms used by nuclear receptors, receptor tyrosine

kinases, and G-protein coupled receptors. Classify which type of hormone signal utilize

these signal pathways.a. Nuclear Receptors:

i. Transcription activating domainii. DNA-binding domain


16/40

iii. Ligand binding domainiv. Inactive form:

1. Inhibitory protein attached to COOHv. Active Form:

1. Inhibitory protein falls off

2.

Ligand surrounded by ligand binding domain + COOH3. Coactivator proteins attach4. DNA binding domain binds to DNA at receptor binding element

vi. Ex: AcHb. Tyrosine Kinase Receptors:

i. Outside: binding site for hormoneii. Inside: enzymatic activity

iii. Receptor dimerizes to get active catalytic subunit1. Kinase activity occurs on dimers on cytosolic side

2.

Autophosphorylation occurs by taking P from ATPiv. Ex: EGF and insulin receptors

c.

GPCR:i.

Least active receptor

ii.

3 subunitsiii. Regulates cell function using secondary messengers

iv. Ex: Glucagon receptors

4. Be familiar with components of G-protein signal transduction pathway. Summarize key

steps in process by which pathway is turned off and on

a. Signal molecule attaches to GPCRb. G-protein activated part attaches GTP and dissociates

c. -part interacts activates effector protein (some cases adenylyl cyclase)d. To turn off: GTP is hydrolyzed to GDP dissociates from effector

5. Diagram key steps of second messenger system involving adenylyl cyclase, generation of

cAMP and activation of cAMP-dependent protein kinase


17/40

a.

phosphate put on hydroxyl side of side chainb.

Phosphorylation by protein kinases changes activity of proteins

6. Describe second messenger system involving phospholipase C and generation of

Diacylglycerol and IP3. Recognize role of calcium in intracellular signaling.a. DAG: activates PKC

b. IP3: increases cytosolic Ca2+c. Phospholipase C acts on lipids (PIP2phosphatidylinositol 4,5 bisphosphate)

i. Cleaves it into DAG and IP3


18/40

7. Concepts and mechanisms involved in covalent modification of proteins by protein

kinases. Understand how protein phosphatases act to reverse protein phosphorylation

and maintain dynamic balance with kinases.a. Each protein kinase has specific activator (ex: cAMP) and distinct substrate

requirements for particular amino acid sequences

b.

Most kinases can phosphorylate multiple substrate proteinsc. Regulatory system:i. Phosphoprotein phosphatases controls phosphorylation state

ii. Steady-state balance determined by balance of kinase and phosphataseiii. Kinase = phosphorylates

iv. Phosphatases: de-phosphorylates

G Protein Activators:

Gs:o Norepinephrineo Epinephrine

o Glucagon

Gi:

o Norepinephrineo Prostaglandins

o Opiates

Gq:

o Ach

o Epinephrine


19/40

Excitation: Action Potential

1. Main characteristics and properties of action potentials in nerves/musclesa. All or none

b. Non-decremental

c.

Unidirectionald. Both Passive and Active processes:i. Passive: local currents

ii. Active: regeneration of action potential involving Na+ channelse. Contains overshoot in depolarization

i. Time during which interior of cell is positiveii. Magnitude of max. positivity

f. Muscles:i. more neg. resting potential (-90)

ii.

depolarizing afterpotentialeven though it is neg. still called depolarizing

because it is still relatively more positive to resting potential

g.

Neurons:i.

about -70

ii.

hyperpolarization afterpotentialh. Cardiac cells: AP lasts 200ms

2. Common property of all stimuli for action potentials

a. All stimuli require injecting positive electrical current

3. Local responses caused in cells by an injection of currenta. Local responses caused if stimuli only reaches subthreshold

b. NOT all or nonec. Can be decremental

d.

Can propagate in any directione. Defined by passive electrical properties

4. Ion movements during depolarizing and repolarizing phases of action potential

a. Depolarization:i. Na+ moves into cell

ii. Cell becomes more positiveiii. EPD becomes more negative

iv. Amount depolarized depends on eq potentialgoes until EPD = 0b. Repolarizing:

i. K+ moves out of cellii.

Large EPD for K+ once Na+ at equilibrium

5. Role of feedback (pos. and neg.) in producing Action potential

a. Depolarization = positive feedback (fast, rapid)i. Stimulus causes depolarization locally

ii. Na+ channels eventually open causes further depolarizationb. Repolarization = negative feedback (stabilizes)


20/40

i. At some point during depolarization, permeability to K+ increases whilepermeability to Na+ decreases reduced depolarization

6. After-potential and refractoriness

a. Absolute refractory:

i.

No stimulus can cause APii. Due to Na channel inactivationb. Relative refractory:

i. Na+ channels have recoveredii. No AP can be produced b/c it is below resting potential

iii. Na channels reopen, but more K channels are open and K channels are slow toclosehyperpolarization

7. Role of Ca2+ in ventricular muscle AP

a.

Allows AP to be prolonged

b. Has a characteristic plateau

c.

Ca2+ channels are slow to open and close

longer AP


21/40

Propagation of Excitation

1. Electrical records obtained with intracellular and extracellular electrodesa. Extracellular electrodes:

i. Used to measure propagation of AP down axon

ii.

Pair of electrodes places on axon on various locations

records propagationiii. 2 characteristics:1. 2 or more phases

2. Smaller amplitude cell membrane is only separator of charge fromelectrodes, thus less potentialless potential difference

2. Spatial propagation as a consequence of regenerative current injection

a. Stimulus caused by injections cause local depolarization at firstb. Further injection causes AP which results in spatial propagation

3. Importance of refractory periods for unidirectional propagation

a.

So it will not go bidirectional

cannot go backwards, only away from injection siteb.

Because of refractory period, previously stimulated regions cannot be excited again

and thus can only go unidirectional

4. Spatial factors affecting propagation. Relationship between space constant and speed of

propagation

a. Length Constant depends oni. Specific Resistance of Resting Membrane (Rm)

1. Greater resistance (fewer open channels) = greater constantii. Longitudinal, internal resistance (axon diameter) (Ri)

1. Smaller internal resistance (greater diameter) = greater constantiii. Greater constant = faster propagation

5. Temporal factors affecting propagationa. Density of Na channels

i. higher density = faster propagationii. positive feedback kicks in faster

b. Specific membrane capacitance (membrane thickness)i. Lower (thick membrane) = faster


22/40

ii. Higher = more current needed to reach threshold = slower propagation

6. Myelin. Structural differences between myelinated and non-myelinated axons that

determine the greater speed of propagation in myelinated axons

a. Myelin in PNS by Schwann cells

b.

Fastest conducting nerve fibers = myelinatedc. Myelinated structure:i. Tight, insulating cuff

ii. Leaves open narrow regions = nodes of Ranvieriii. Few channels in membrane under myelin

iv. Na channels concentrated near nodes of Ranvier = faster propagationd. Factors increasing propagation speed in myelinated axon:

i. Spatial:1. Few channels under myelin (high Rm)

2.

Large diameter (low Ri)

ii. Temporal:

1.

Thick membrane (low Cm)2.

High density of Na channel in nodes

7. Saltatory conduction

a. Due to fast conduction is discontinuous = action potential jumps node to nodeb. Na channels only at nodes so allows AP to jump

c. Efficient since it saves internode from outflow of K+ since only nodes have torepolarize, not the entire axon. Thus, it saves the axon from having to repolarize

throughout the whole axon, but instead just at the nodes.

8. Classification of peripheral nerve fibers


23/40

9. Safety factor for conduction

a. Safety factor: amount of nodes one node can activate before losing action potentialb. High safety factor allows action potential to continue more likely in event of injury

10.Effects of demyelinating diseases, therapeutic effects of K+ channel blockers

a.

Multiple sclerosis:i. Sever impairment of nervous functionii. Loss of myelin

1. Increases Cm (myelin affects membrane not axon thickness)2. Reduces Rm

3. Na channels in nodes become dispersedb. 4-aminopyridine:

i. K channel blockerii. Improves ability to control movement

11.Electrical propagation of action potentials from cell to cell

a.

Uses gap junctions to propagate action potential (electrical mechanism)b.

Spans two membrane bilayers of 2 difference cells

c.

Ex: heart muscle

12.Electrical vs Chemical Mechanismsa. Electrical:

i. Use special junctions called electrical synapsesii. Allows cells to work and contract synchronously like in the heart

b. Chemical:i. Occurs in synapses

ii. Uses chemical transmitters


24/40

Neural Control of Organs I:

1. Subdivisions of the CNS vs. PNS, sensory vs motor, somatic vs viscerala. CNS:

i. Parts:

1.

Brain2. Brainstem3. Terminal cranial (CN 0)

4. Olfactory cranial5. Optical cranial

6. Retina7. Spinal Cord

ii. Oligodendrocytes myeliniii. Axons cannot regenerate

b.

PNS:

i. Parts:

1.

Ganglia, nerves from CN III-XII2.

Spinal Nerves

ii.

Schwann Cells myeliniii. Axons can regenerate (if spinal cord cut cannot regenerate)

c. Sensory vs Motor:i. In both CNS and PNS

ii. Sensory:1. Afferents

2. In dorsal root ganglion of PNSiii. Motor:

1. Acts on organs, cause action2. No immediate feedback

3.

Anterior horn of spinal cord4. Motor axons come from CNS

5. Body of motor cells in spinal cordd. Somatic vs. Visceral

i. Somatic = motor, moves in conscious wayii. Visceral = unconscious actions

1. ex: innervation of heart, swallowing


25/40

2. Differences among somatic and autonomic visceral motor systems

3. Subdivisions of autonomic visceral motor system

a. Parasympathetic:

i. AcHii. Originates from midbrain + sacral

iii. Preganglionic = longiv. Postganglionic = short

v.

Uses all muscarinic Ach receptorsb. Sympathetic:

i. Epinephrineii.

Originates from thoracic + lumbar

iii. Preganglionic = short (muscarinic Ach receptors)iv. Postganglionic = long (norepinephrine receptors, except Sweat glands: Ach)

1. Adrenal medulla secretes epinephrine/norepinephrine into blood


26/40

4. Role of reflex arc: (connection between neurons)a. Occurs in response to stimulus without conscious influence

b. Most nervous system acts by reflexesc. Unconsciousallows automatic regulation

d. Somatic Reflex: muscle/tendon

i.

Ex: knee jerk (1 synapse)e. Visceral Reflex: at level of organs:f. Short (mono) and Long (di/polysynaptic) Reflex

g. Intrinsic (born with) and Acquired Reflex

5. Role of autonomic control centers in brain:

a.

Medulla + Hypothalamus integrate 3 systems:

i.

Autonomicii. Endocrine

iii. Part of CNS that deals with motivation and emotion

6. Sensory inputs of autonomic control centers in brain:

Leptin and insulin goes through

BBB using specific transportmechanism b/c insulin is big

peptide


27/40

7. Circumventricular organs of brain:a. Median Eminence:

i. 3rdventricleii. Does not have BBB

iii. Contains arcuate nucleus

iv.

Measures hormone levels in bloodv. Controls basal level hormonesvi. Directs release of hypophyseal hormones

vii. Part of inferior hippocampusb. Organ Vasculosum of Lamina Terminalis:

i. Determines osmolarity of serumii. Can make you thirsty

iii. Supraoptic nucleus: fluid electrolyte balanceiv. Preoptic Nucleus: regulates LHRH

v.

Suprachiasmatic nucleus:

1. tells pineal gland to release melatonin

2.

releases GHc.

Subfornical Organ:

i.

In front of foramen of Monroeii. Contains hippocampal mammillary tract

iii. Contains angiotensin II receptors1. Responds to decreased concentration of serum

iv. Projects to supraoptic organ + lamina terminalisv. Releases ADH

d. Pineal Gland:i. Highly vascular

ii. Releases melatonin into CSF of 3rdventricle1. mediated by epiphyseal cells

e.

Under Posterior Commissure Subcommissural Organi. BBB free area

ii. Capillaries are not fenestratediii. Epithelial gland cells

iv. Located at beginning of aqueduct of Sylviusv. Controls 3rdand 4thventricle CSF movement or compounds

f. Area Postrema:i. Floor of 4thventricle

ii. Modified astrocyteiii. Vomiting center of brain

iv. Ionotropic receptorsv.

Removes toxins in body

vi. Most critical chemosensor in brainvii. Gut peptides from gut in bloodstream sensed by postrema

g. Posterior Pituitary

h. Sensory: area postrema, OVLT, subfornical organi. Secretory: posterior pituitary, median eminence, pineal gland, subcomissural organ


28/40

j. Features:i. Fenestrated between endothelial cells lining vasculature

1. no tight junctions2. regular CNS cells have tight junctions

ii. High blood volume to tissue weight ratio

iii.

High density of receptors for blood circulating signals of autonomic state

Important Table:


29/40

Neural Control of Organs II:

1. Synaptic and non-synaptic modes of neurotransmissiona. Synaptic:

i. Fastest

ii.

In CNSiii. Few junctionalb. Non-synaptic:

i. Majority of transmission in nervous systemii. Junctional = paracrine

1. Close (fast)2. Wide (slow)

iii. Remote = endocrine1. CSF (fast)

2.

Via Blood (slow)

iv. Ex: autonomic neural control of smooth muscle, immune, epithelial, and

endothelial cells

2. Types of intercellular signaling: juxtacrine, autocrine, paracrine, and endocrinea. Juxtacrine: transmitted via protein or lipid components of membrane and is capable of

affecting either the emitting cell or cells immediately adjacentb. Autocrine, Paracrine, Endocrine: already discussed previously

3. Neuronal and non-neuronal synapses:

a. Neuronal synapse: at point where two communicating cells meeti. Intercalated discs in heart is similar to synapses in neurons

b. Non-neuronal: point where T cell comes to attack invading cell

4.

Mechanisms of synaptic transmission: electrical and chemicala. Electrical:

i. Direct flow of current through gap junctionii. Passes through specialized proteins connexons

1. 2 parts2. Each part made of 6 connexins

3. Connection of two connexons form gap junction4. Feature of multicellular

organismsiii. Uncommon, mostly in CNS

iv. Rapid signal conductionb.

Chemical:

i. Majority of synapsesii. Uses neurotransmitters to relay info


30/40

5. Nerve terminals: varicosities, buttons, end plates, En passant varicositiesa. End plates:

i. Specific arrangement of buttonsb. En Passant Varicosities:

i. Characteristic for visceral innervation

ii.

In smooth muscle cells of gutiii. Principle for neural innervation, not synapsesiv. Neural transmitter released from varicosities

v. Paracrinevi. Smooth muscles electrically coupled by gap junctions (2 connexons)

6. Neuroeffector junctions: somatic, visceral, vascular

a. Somatic:i. neuromuscular junction

ii.

use Ach (barely found in plasma)

b. Visceral/Vascular:

i.

Doesnt have to be synapticii.

Terminal portion of autonomic nerve fibers are varicose

iii.

Transmitters released from varicosities at various distance from effector celliv. No structural post junctional specialization on effector cells

v. Receptors for neurotransmitters accumulate on cell membrane at closejunctions

c. Difference between visceral/vascular:i. Vascular: close to blood vessels

ii. Visceral: specific to smooth muscles + organs

7. Somatic neuroeffector junction (neuromuscular junction) is a chemicalsynapsea. Skeletal muscle fiber innervated by single -motorneuron

b.

All fibers innervated by same axon = motor unitc. Neuromuscular junction formed by axon = end plate

d. Presynaptic button:i. covered by Schwann cells

ii. in synaptic cleft (depression on muscle fiber)iii. contains Ach

iv. Ca2+ influx causes vesicles to fuse with presynaptic membrane1. Low extracellular Ca2+ = reduced Ach released

e. Sarcolemma of end plate has nicotinic Ach receptors

8. Synthesis and recycling of acetylcholine (AcH): ChAT and AChEa.

Ach is pentamer (5 subunits)

b. Inside presynaptic button:i. Cholineacetyltransferase (ChAT) reacts with choline Ach

ii. Ach releasedc. Ach binds to postsynaptic receptor

d. AChE (acetylcholinesterase) unbinds Ach from receptor


31/40

9. Nicotinic Ach receptor is a ligand-gated channel

10.Quantal nature of synaptic transmission. Mechanism of ACH release

a. Ach is packaged in discrete vesicles

b.

Integer number of vesicles is releasedc. Apparent in low Ca2+ concentrationless Ach is released able to countd. Mechanism:

i. Specific transport proteins in vesicle membrane use energy of H+ gradient toenergize uptake of Ach into vesicles in presynaptic button

ii. Action potential arrives involving Na-K channelsiii. Depolarization opens Ca2+ channles Ca2+ enters

iv. Ca2+ triggers fusion of vesicles with presynaptic membrane Ach releasedv. Termination:

1.

Enzyme

2. Reuptake

3.

Diffusion away from synapse

11.Drugs affecting neuromuscular junction. Diseases of nicotinic AChRa. Tetrodotoxin

i. Blocks Na channelsii. No depolarization

b. Molluscan:i. Blocks Ca2+ channels

ii. Prevents release of Achc. Botulinum

i. Binds to presynaptic membraneii. Prevents release of Ach

d.

Curarei. Binds to AChR (receptor of ach)

ii. Prevents binding of ache. Myasthenia gravis

i. Autoimmune diseaseii. Block of AChR by anti-AChR antibodies

iii. Muscle weaknessf. Lambert-Eaton Syndrome:

i. Autoimmuneii. Attack on presynaptic Ca2+ channels

12.

A two-transmitter view of autonomic nervous system

a. Sympathetic:i. Preganglionic: Ach ionotropic nicotinic receptors

ii. Postganglionic: NE metabotropic and -adrenergic receptorsb. Parasympathetic:

i. Preganglionic: Ach ionotropic nicotinic receptorsii. Postganglionic: Ach metabotropic muscarinic (G-protein) receptors


32/40

13.Adrenaline. Nor- or not, whats the difference? NANC transmitters

a. Epinephrine = adrenalinei. Increases 50x in stress

ii. Mostly from adrenal medulla

iii.

Hormone, not neurotransmitterb. Norepinephrine:i. Mainly produced by nerve terminals in vasculature by varicosities

ii. Little produced by adrenal medulla

c. NANC (non-adrenergic, non-cholinergic) autonomic transmitters: many in guti. Neuropeptide Y

ii. Nitric Oxide

iii.

Vasoactive Intestinal Peptideiv. ATP

Question marks replac

by: up, down, up, upStimulatory receptors

and 2


33/40

14.Co-transmission at nerve terminals of both pre and postganglionic neurons of

autonomic motor systema. Ganglionic Synapse (Ach)

i. Ach can activate both nicotinic and muscarinic receptors

ii.

Produce fast and slow postsynaptic responseb. Neurovascular Junction (Norepinephrine)i. 1-adrenergic receptor on postsynaptic area vasoconstriction

ii. 2-adrenergic receptor on presynaptic membrane to inhibit further releasec. Secretomotor Junction (Ach + VIP)

i. Co-transmissionii. Parasympathetic postganglionic nerve terminals in salivary gland release Ach

and vasoactive intestinal peptide (VIP) to control secretion


34/40

Muscles: Conversion of Chemical Energy (ATP) into Mechanical Force

1. Types of muscle tissue: skeletal, cardiac, and smooth.a. Skeletal:

i. Multiple nuclei

ii.

Striatediii. Responsible for voluntary movementiv. Innervated by somatic motor system

v. Enclosed by tough connective tissue to form musclevi. One transmitter, one synapse

b. Cardiac:i. Multiple nuclei

ii. Striatediii. Cells branched

iv.

Cell connected by intercalated discs (electrical current can flow)

v. Only in heart wall

vi.

Allows involuntary heart beatc.

Smooth:

i.

Single nucleusii. NOT striated

iii. Cells held together by tight junction and tapers at endsiv. Located in hollow organs (blood vessels, GI tract, bladder)

v. Involuntary movements (peristalsis)


35/40

2. Membrane architecture of striated musclesa. Sarcomere: basic unit of skeletal muscle (1-2 microns)

b. Sarcomere < Myofilaments < Myofibrils < Muscle fiber < Muscle fasciculusc. Each fiber surrounded by electrically polarized membrane sarcolemma

d. T-tubules invaginate from sarcolemma and form junctions with Sarcoplasmic

Reticulume. T-tubule every 2 micronsf. SR stores Ca2+

g. SR network surrounds myofibrilsh. Striatedtriads (2 SR + T-tubule)

3. Difference between Cardiac and Skeletala. Cardiac:

i.

Smaller cells

ii. T-tubules:

1.

Shorter and broad2.

Diad

3.

Encircle sarcomere at Z lines instead of overlapiii. SR

1. lacks terminal cisternae2. tubules contact both cell membrane and T-tubules

iv. intercalated discs (gap junctions + desmosomes)v. Functional syncytium

1. Chemically, mechanically, electrically connected2. Resembles enormous muscle cell

4. Structural differences between striated and smooth muscles

a.

Smooth:i. No t-tubules

ii. No myofibrilsiii. No sarcomeres

iv. Contracting cell twists like corkscrew (fishnet contraction)v. Has dense bodies:

1. Where filaments attach2. Part of intermediate filament network (cytoskeleton)

3. Binds adjacent muscle cells4. Allows transmission of contractile forces from cell to cell

vi. Many not innervated by motor neuronsvii.

Multiunit:

1. resemble skeletal and cardiac2. neural activity produces AP

3. Location: iris, male reproductive tract, walls of large arteries4. Not in digestive tract

viii. Visceral:1. Arranged in sheets or layers


36/40

2. Connected by gap junctions3. Have rhythmic cycles in absence of neural stimulation (digestive)

4. Spontaneous depolarization

5. Importance of intracellular Ca2+ signaling for muscle contraction

a.

Ca2+ is secondary messengerb. Increase in Ca2+ usually indicates muscle contractionc. Ca2+ is released from terminal cisterns of SR once AP reaches it

i. AP reaches DHPR (voltage sensor) on T-tubuleii. Communicates with RyR, which releases calcium at SR

d. Ca2+ diffuses to actin and myosin filamentse. Ca2+ binds to troponin C, which is on tropomyosin

f. Binding allows tropomyosin to move away from actin myosin can now bindg. Rowing motion begins

h.

High Ca2+ concentration outside SR causes calcium-ATPase to be activated

i. Pump brings Ca2+ back to SR tropomyosin restored to blocking binding sites

6. Excitation-Contraction Coupling (ECC) in the 3 kinds of muscles. Link between

excitation and intracellular Ca2+ release. Major differences in mechanisms ofintracellular Ca2+ release.

a. Excitation-Contraction Coupling: process of converting excitation through AP orelectrical event to a force (mechanical event) due to myosin/actin.

b. Skeletal ECC:i. Steps:

1. Conformational change of DHPR (voltage sensor)2. Structural rearrangement of DHPR

3. RyR1-DHPR interaction.4. RyR1 channel opens

ii.

AP ends by time calcium channels open (peak Ca2+ at 5ms)iii. Peak tension = 25ms

iv. Gating potential determines AP, not Ca2+ that moves through itv. Depends on direct coupling of DHPR/RyR1

vi. Action Potential permeability of sarcolemma to extracellular Ca2+ ions


37/40

c. Cardiac ECC:i. Steps:

1. Conformational Change of DHPR2. Structural rearrangement of DHPR

3. L-type Ca2+ channels open Ca2+ enters cell

4.

Ca2+ binds to RyR2 causing structural rearrangement5. RyR2 channels openii. Calcium induced/Calcium released NOT by voltage

iii. Calcium influx vital to EcCiv. AP lasts much longer and plateaus

v. Calcium channels open and close during AP plateauvi. Peak tension = 150 ms

vii. Positive feedback calcium moving inwards induces more calciumviii. Contraction

1.

Determined by pacemaker cells

2. Neural stimulation not needed

3.

Done through automaticity4.

Cannot undergo summation or tetanic contraction


38/40

d. Smooth ECC:i. Action Potential NOT needed stimulated by (either/or)

1. Depolarization (electromechanical)2. Hormones (chemo-mechanical)

ii. Triggered by Ca2+ ions from extracellular fluids

iii.

No linkage between length and forceiv. Myogenic tone:1. If pulled will contract

2. Regulated by mechanical regulator in cell instead of externalactions

v. No troponinvi. Myosin is activated by phosphorylation following rise in Ca2+

1. Actin is not acted upon like in skeletal muscles2. Myosin Light Chain Kinase (MLCK) is activated when it binds to

calmodulin that is bound to Ca2+

3. MLCK phosphorylates myosincan power stroke

4.

Dephosphorylation done by phosphatase (MLCP)a.

Inhibited by hormones

vii.

Force is sustained after stimulation by hormone, but not by depolarizationviii. Ca2+ sensitization and L-type Ca2+ channels maintain contraction

ix. If hormone used, less Ca2+ needed due to reduced control of MLCP

7. Contractile machinery in 3 kinds of muscle. Proteins involved. Actin-myosin interaction

cycles. Role of latch state in smooth muscle. Electromechanical and chemo-mechanical

ECC in smooth muscle.a. Latch State (smooth muscle)

i. Rather than having tetanic contraction, smooth muscles use a latch systemto allow prolonged contraction without constant use of ATP

b. Everything else is mentioned in questions #6


39/40

Extra Info:

Peripheral Proteins: remove through acid or salt

Integral Proteins: remove through detergent

Solution: molecular mixture, homogeneous

Body Fluid Compartment:o 60% body weight = water

o 40% = ICF

o 20% = ECF

RBC in Solution:o Hypotonic lyseo Hypertonic shrivel

Smooth Muscle is often near entrance to capillaries

o Regulates amount of blood flow into each vesselo If tissue oxygen starved smooth muscle relaxes blood flow increasesmore

oxygen

Hyperkalemia: high K+ serum levelso Causes resting potential to be raisedo Muscles are depolarized, but inactivation gates of Na+ are closed thus no action

potential can occur

o Ultimately, muscle weakness

Reflection Coefficient:o If 1 solute is impermeable water flows (ex: albumin, large particle)o If 0 solute is completely permeable no water flow (ex: urea)

Poisoning Na-K Pump:

o Inhibits Na-Ca exchange: Because more Na+ remains intracellularly, Na+ from outside will not go

down its gradient and thus no Ca2+ will move outo Inhibit Na-glucose cotransport:

Na+ will remain intracellularly, thus co transport cannot happen since no Na+

gradient

o Decreases Na+ out of cell decreases resting membrane potential once passivetransport of Na and K takes placeinhibits secondary active transport

Inhibitors of Na-K Pump:

o Causes increase in cell volume due to osmotic entry of watero Ouabain

o Digitalis

o Low pH

Activators of Na-K Pump:o Insulino Aldosterone

Tetanus:

o Increases Ca2+ levels intracellularly

o Causes extension of cross-bridge cycling

o Muscles cannot relax Tetanus

Force-Length Relationship of Muscles:


40/40

o Consequence of sliding filament mechanism

o Max isometric contraction = 22.5 micrometers in sarcomere length for skeletal

o Stretching cardiac muscles increase force of contraction (Frank Starling Law)

o Active tension: force developed from contraction of muscle

Proportional to number of cross-bridges formed

Max overlap of thin/thick = max tension Stretched muscle = less overlap

o Passive tension: tension by stretching muscle

Extracellular Signals:

o Endocrine: insulin, epinephrine

o Local: cytokines, histamines, prostaglandinso Neurotransmitters: Ach, glutamate

Effects of Signal Transduction:

o Long Term: alteration in gene expression alters protein synthesis (ex: steroids) Nuclear receptors interact with DNA elements + regulatory proteins

o Short Term: altering protein function (phosphorylation)

Formation and Degradation of cAMP:o Adenylyl Cyclase: formation

o cAMP phosphodiesterase: degradation

Protein Kinases:

o Tetramer

o PKA holds 4 cAMP

o Inactive forms are regulators (2 inactive, 2 active)

o Phosphorylates on serine, threonine, or tyrosine residues

Calmodulin

o Binds 4 Ca2+ ions

o Inactive when folded up

Motor Neuron vs. Skeletal Muscle Fiber Action Potential:o Muscle Fiber more negative (-90)

o On down end of AP: Motor Neuron: hyperpolarization

Skeletal Muscle: depolarization (getting more negative, but always remains

more positive in relation to resting potential)

Sodium Channel Blockers and Anesthetics promote refractory period

o Acts on inactivation gates

o During refractory periods Na+ inactivation gates closed

Multiple Sclerosis:o Loss of mylin

o

Treatment K Channel Blockers (4-aminopyridine)

Cystic Fibrosis:o Mutation of CFTR (calcium channel) deletion of phenylalanineo Secretion of Cl- and water is reducedmucous secretion

o Na+ channels on apical side are increased increased water and Na+ reabsorption

o Treatment:

Physiology Exam 1 Lecture Objectives

Documents

Transcript of Physiology Exam 1 Lecture Objectives