HUMAN PHYSIOLOGY PART 3HOMEOSTATIC MECHANISMS AND CELLULAR COMMUNICATION(CHAPTER 7 VANDER)

John Paul L. Oliveros, MD

General Characteristics Homeostasis

Denotes the relatively stable conditions of the internal environment

Steady State A system in which a particular

variable is not changing but energy must be added continuously to maintain this variable constant

Setpoint/operating point Steady-state temperature of the

thermoregulatory system “Stability of an internal

environmental variable is achieved by balancing of inputs and outputs “

General Characteristics Negative-feedback

system An increase or decrease in

the variable regulated brings about responses that tend to move towards the opposite direction of the original change

Most common homeostatic mechanisms in the body

e.g. Dec in body temp responses to inc body temp to original value

General Characteristics Positive-feedback Mechanism

Initial disturbance in a system sets off a train of events that increase the disturbance even further

Does not favor stability Abruptly displaces a system away from its

normal set point e.g. Uterine contractions during labor

General Characteristics “Homeostatic control systems do not maintain complete constancy of

the internal environment in the face of continued change in the external environment, but can only minimize changes”

As long as the initiating event continues, some change in the regulated variable must persists to serve as a signal to maintain to homeostatic response

Error signal: persisting signal needed to inform our body that initiating event is still present and that there is still a need to maintain a response

Any regulated variable in the body has a narrow range of normal values

The range depends on: magnitude of changes in the external conditions Sensitivity of the responding homeostatic system

the more precise the regulating system, the smaller the error signal needed, the narrower the variable range

General Characteristics Reset of set points

The values of that the homeostatic control systems are trying to keep relatively constant can be altered

e.g. Fever higher temp is adaptive to fight infection

e.g. Decrease serum Iron during infection to deplete infectious organisms of iron required for it to replicate

Set points may also change on a rythmical basis

Set points may also change due to clashing demands of different regulatory systems

General Characteristics Feedforward regulation

Frequently used in conjunction with negative-feedback systems

Anticipates changes in a regulated variable

Improves speed of the body’s homeostatic responses

Minimizes fluctuations in the level of the variable regulated

Reduces deviation from the set-point.

e.g. Skin nerve receptors for temp detects cold weather and activates body’s thermoregulatory systems before actual decrease in body temp

Components of homeostatic control systems

Reflexes Local homeostatic responses

Reflexes Reflexes

Stimulus response sequence

A specific involuntary, unpremeditated, unlearned “built-in” response to a particular stimulus

However, it may be learned or acquired, but distinction may not be always clear

Reflex arc Pathway mediating a reflex

Reflex Arc Components

Stimulus Detectable change in the internal or external environment

Receptor Detects the environmental change AKA detector Produces a signal in response to a stimulus

Afferent pathway Pathway traveled by the signal to the Integrating center

Integrating center Receives signals from many receptors responding to different stimuli Integrates numerous bits of information Output of the integrating center reflects the net effect of the total afferent input

Efferent pathway The pathway of information from integrating center and effector

Effector A device whose change in activity constitutes overall response of the system

Reflexes

Reflexes All body cells act as an effector in homeostatic reflex 2 major classes of effector tissues:

Muscles glands

2 Reflex systems Nervous system

e.g. Thermoregulatory reflex Endocrine system

Glands: integrating center receptor

Hormones Blood borne chemical messenger May serve as an efferent pathway

Local Homeostatic Response Local homeostatic response

Another group of biological responses of great importance for homeostasis

Initiated by a change in the internal or external environment (stimulus)

Induces alteration in cell activity with the net effect of counter acting the stimulus

Local response is the result of sequence of events proceeding from a stimulus

However, the entire sequence of events occurs only in the area of the stimulus

Provide individual areas of the body with mechanisms for local self regulation

e.g. Skin damage local cellular release of protective chemicals

Intercellular Chemical Messengers Vast majority of

communiction between cells is performed by chemical messengers

Intercellular communication is essential for reflexes, local homeostatic response and therefore to homeostasis

3 categories of chemical messengers Hormones Neurotransmitters Paracrine agents

Intercellular Chemical Messengers Hormone

Enables the hormone secreting cell to act on its target cell

Delivered by blood Neurotransmitter

Chemical messengers secreted by nerve cells Released from nerve cell endings and diffuses into

the ECF in between nerves/cells to act upon the 2nd Nerve cell or effector cell

Neurohormones Nerve cell secretions that enter the bloodstream to act on

cells elsewhere in the body

Intercellular Chemical Messengers Paracrine Agents

Synthesize by cells and released to the ECF in presence of a stimulus

Diffuse into the neighboring target cells

Inactivated rapidly by locally existing enzymes

Do not enter the blood stream in large quantities

Autocrine Agents Chemical secreted by a cell

acts on the same cell Frequently, chemical

messengers may act as paracrine or autocrine agents

Seemingly endless list of paracrine and autocrine agents identified Nitric Oxide Fatty acid derivatives Peptides and AA derivatives Growth factors Etc., etc.

Stimuli for release are extremely varried Local chemical changes (e.g

change in O2 levels) Neurotransmitters hormones

Intercellular Chemical Messengers Eicosanoids

Paracrine/autocrine agents that exert a wide variety of effects in virtually every tissue and organ system

A family of substances produced from arachidonic acid Polyunsaturated FA Present in PM phospholipids

Groups: Cyclic endoperoxides Prostaglandins Thromboxanes leukotrienes

Intercellular Chemical Messengers Eicosanoids

Beyond Phospholipase A2, the eicosanoid pathway found in a particular cell determine which eicosanoids the cell synthesizes in response to a stimulus

Each major eicosanoid subdivision has more than 1 member Structural molecular difference designated by a letter (e.g. PGA, PGE) Further subdivisions by number subscripts (PGE2, PGE3)

Once synthesized in response to a stimulus, they are immediately released and act locally

Drugs that influence eicosanoid pathway Aspirin:

Inhibits cyclooxygenase Blocks the synthesis of endoperoxides, prostaglandins and thromboxanes

NSAIDs: Also blocks cyclooxygenase Reduce pain, fever, inflammation

Adrenal Steroids: Used in large doses Inhibits phospholipaseA2 Block production of all eioosanoids

Processes Related to Homeostasis Acclimatization Biological rhythms Regulated Cell Death: Apoptosis Aging Balance in the homeostasis of chemicals

Acclimatization Adaptation:

Denotes a characteristic that favors survival in specific environments Homeostatic control systems are inherited biological adaptations

Acclimatization: A type of adaptation in which there is an improved functioning of an already

existing homeostatic system An individual response to a particular environmental stress is enhanced

without a change in genetic endowment Due to prolonged exposure to stress e.g. Sauna bath

1st day : 30 min 1 week : 1-2 hrs/day 8th day: earlier sweating, more profuse sweating, body temp does’t rise as much

Usually completely reversible Once stress is removed, body reverts back to preacclimatization condition Developmental acclimatization:

Acclimatization is induced early in life (critical period) and becomes irreversible

Biological Rhythms Circadian rhythm

Most common type Cycles approximately

every 24 hrs Body functions

Waking and sleeping Body temperature Hormone

concentrations Excretion of ions in

urine Etc.

Biological Rhythms Add another anticipatory component to homeostatic control systems Act as a feed-forward system operating without detectors Enable homeostatic mechanisms to be utilized immediately and

automatically activation at times when a challenge is more likely to occur but before it

actually does occur e.g. Decrease urinary K+ excretion at night

Entrainment: Setting of the actual hours by the body with timing cues provided by

environmental factors e.g. Experiment done on chambers with time to ‘lights off” controlled wake-

sleep cycled persisted but at 25 hrs cycle (free-running rhythm) Environmental cues:

Light-Dark cycle: most important environmental cue External environmental temp Meal timing Many social cues

Biological Rhythms Phase shift rhythms

Reset of the internal clock by environmental time cues Jet lag

Happens when one jets from east or west to a different time zone

Sleep-wake cycle and other circadian rhythms slowly shift to the new light-dark cycle

Symptoms may be caused by disparity between external time and internal time

Symptoms: disruption of sleep, gastrointestinal disturbances, decreased vigilance and attention span, general feeling of malaise

Biological Rhythms Neural basis of body rhythms

Suprachiasmatic nucleus A collection of nerve cells in the hypothalamus Functions as the principal pacemaker (time clock) for

circadian rhythms Probably involves the rhythmical turning on and off of

critical genes in the pacemaker cells Input: from eyes and many parts of the nervous system Output: other parts of the brain

Pineal Gland: One of the outputs of the pacemaker Secretes melatonin (usually at night)

Biological Rhythms Have different effects on the body’s

resistance to various stresses and responses to different drugs

Heart attack: 2x in the first hours of waking

Asthma: usually at night Asthma meds: usually given at night to

deliver a high dose of med between 12am-6am

Apoptosis Regulated cell death The ability to self-destruct by activation of an

intrinsic cell suicide program Important role in the sculpting of a developing

organismand in the elimination of undesirable cells (e.g. Cancerous cells)

Regulation of the number of cells in tissues and organs

Balance between cell proliferation and cell death e.g. Neutrophils die by apoptosis 24 hrs after

being produced in the BM

Apoptosis Occurs by controlled autodigestion of cell contents Endogenous enzymesbreakdown nucleus and DNA

breakdown of organelles Plasma membrane intact to contain cell contents Signal sent to nearby phagocytes eat dying cells Toxic breakdown products are contained no

inflammatory response triggered Necrosis: cell death due to injury release of toxic cell

contents inflammatory response All cells contain apoptopic enzymes maintained

inactive by chemical survival signals sent by neighboring cells, hormones, and extracellular matrix

Apoptosis Abnormal inhibition of Apoptosis:

cancer Abnormal high rate of apoptosis:

degenerative disease (e.g. Osteoporosis)

Aging Physiologic manifestations:

Gradual detrioration in the function of virtually all tissues and organs systems

Deterioration of the homeostatic control systems to respond to environmental stresses

Decrease in the number of cells in the body Decreased cell division Increase cell death Malfunction of remaining cells

Immediate cause: Interference in the function of the cells macromolecules (e.g. DNA)

Aging Decreased cell division

Built in limit to the number of times a cell divides

DNA loses a portion of its terminal segment (telomere) each time it replicates

Genetic and environmental factors Progressive damage

Variability of lifespan: 1/3- genes 2/3- differing environments

Aging Genes

Probably those that code for proteins that regulate the processes of cellular and macromolecular maintenance and repair

Werner’s syndrome: premature aging due to a mutation of a single gene that is critical for DNA replication or repair

Difficulty in determining if changes in the body are due to aging or disease

Can the aging process be inhibited or slowed down? Exerise Balanced diet: reduces formation of free radicals

Balance in the Homeostasis of Chemicals

Balance diagram for a chemical substance

Balance in the Homeostasis of Chemicals

Exception to scheme: mineral electrolytes Can’t be synthesized Do not normally enter thru lungs Can’t be removed by metabolism e.g. Na+

Generalizations of the balance concept: During any period of time, total-body balance

depends upon the relative rates of net gain and net loss to the body

The pool concentration depends not only upon the total amount of the substance in the body, but also upon exchanges of the substance within the body

Balance in the Homeostasis of Chemicals

3 states of total-body balance Negative balance:

Loss exceeds gain amount of substance in the

body is decreasing Positive balance:

gain exceeds loss, amount in body increasing

Stable balance: gain = loss A stable balance can be

upset by alteration of the amount being gained or lost in a single pathway in the schema

Section B: Mechanisms by which chemical messengers control cells

Homeostatic Mechanisms and Cellular Communication

Receptors Chemical Proteins: ligands Receptors:

target cell proteins Binding site Glycoproteins located

Plasma membrane More common Transmembrane CHONs Has segments extracellular, within the membrane, and intracellular Where lipid-insoluble messengers bind

Intracellular Mainly in the nucleus Where lipid soluble chemical messengers bind

Receptors Specificity:

A very important characteristic of Intercellular communication

Cells differ in types of receptors they contain

Frequently, just one cell type possesses the receptor required for the combination with a given chemical messenger

“superfamilies” : group of receptors closely related structurally for a group of messengers

Receptors Different cell types may possess the same receptors for a

particular messenger, but responses to the same messenger may differ Receptor functions as a molecular switch that switches on when a

messenger binds to it e.g. Norephinephrine

Smooth muscle of blood vessel contract Pancreas decrease insulin secretion

A single cell may contain several different receptor types for a single messenger Response different from one receptor to another in the same cell e.g. 2 epinephrine receptor sites in smooth muscle cells of BV

(contraction vs dilation) The degree to which the molecules of a messenger bind to different

receptor sites in a single cel depends on the affinity of the different receptor types for the messenger

Receptors A single cell contains many different receptors for different

chemical messengers Saturation:

response increases as extracellular concentration of the messener increases

Upper limit to responsiveness due to finite number of receptors available that become saturated at a point

Competition: Ability of different messenger molecules that are very similar in

structure to compete with each other for a receptor Antagonist:

drugs that bind on the receptors without activatng them prevent messengers from binding and triggering a response e..g. B-blockers

Receptors Agonist:

Drugs that bind on a particular receptor and trigger the cell’s response as if a true chemical messenger had combined with the receptor

e.g. Ephidrine epinephrine receptors Down-regulation:

High ECF messenger concentration target cell receptors decrease Reduces target cells’ responsiveness to frequent or intense stimulation

by a messenger Local negative feedback mechanism e.g. Insulin glucose uptake decrease insulin receptors

Up-regulation: Cells exposed to a prolongd period of very low concentrations of a

messenger maydevelop many more receptors for the messenger e.g. Denervated muscls contract when injected with small amounts of

neurotransmitter

Receptors Down-regulation

Binding of messengers to receptors endocytosis degradation of receptors

Up-regulation Stores of receptors in IC vessicles insertion via

exocytosis Gene that code for receptors

Alteration of expression during down/up-regulation Receptors may decrease or increase due to a

disease process Myasthenia gavis: aceylcholine receptors in muscles are

destroyed mscle weakness/destruction

Signal Transduction Pathways The sequences of events between receptor

activation and the cell’s response Signal:

Receptor activation Transduction:

Process in which stimulus is transformed into a response

Lipid-soluble messengers: Receptors inside the cell

Lipid-insoluble messengers Receptors in the plasma membrane of cell

Signal Transduction pathways Receptor activation:

Initial step leading to the cell’s ultimate responses to the messenger

Causes a change in the conformation of the receptor Common denominator: all directly due to alterations of

a particular cell protein Changes may be in the form of:

Permeability, transport properties, or electrical state of the plasma membrane

The cell’s metabolism The cell’s secretory activity The cell’s rate of proliferation and differentiation Cell’s contractile activity

Signal Transduction Pathways Pathways initiated by

intracellular pathways Lipid soluble messengers

mostly hormones Closely related

structurally Receptors

Steroid hormone receptor superfamily

Intracellular, mostly in the nucleus

Inactive when not bound to messenger

Activation altered rates og gene transcription

Transcription Factor Receptor + Hormone Regulatory protein that directly

influences gene transcription Response element:

specific sequence near a gene in DNA where the receptor binds

Increases the rate of the gene’s transcription into mRNA

mRNA direct synthesis of CHON encoded by the gene

One gene may be subject to control by a single receptor

In some cases, transcription of the gene/s is decreased by the activated receptor

Signal Transduction Pathway

Signal Transduction Pathway Pathways initiated by Plasma

membrane receptors First messengers

Intercellular chemical messenger Hormones, neurotransmitters,

paracrine agents Second messengers

Non protein substance/enzymatically generated cytoplasmtransmit signals

Protein kinase Any enzyme that phosphorylates

other CHONs by transfering them a PO4 group from ATP

Changes the activity and sonformation of the CHON

May involve may CHON kinase

Signal Transduction Pathway Receptors that Function as ion channels

Receptor constitute an ion channel Activation opening of channels diffusion

of specific channels change in membrane potential cell’s response

Ca++ channel increase cytostolic Ca++ conc. essential for signal transduction pathways

Signal Transduction Pathways Receptors that function as enzymes

With intrinsic enzyme activity Almost all are protein-kinases, mostly tyrosine-kinases Binding of messenger change in receptor

conformation activation of enzymatic portionautophosphorylation of tyrosine groups phosphotyrosine “docking sites” for other CHONs Cascade of signaling pathways within the cell

Guanylyl cyclase receptor: Catalyzes formation of cGMP (2nd messenger) activation of

cGMP-dependent protein kinase phosphorylation of a CHON cell’s response

Signal Transduction Pathways Receptors that interact with Cytoplasmic

JAK Kinases Receptor with intrinsic enzmatic activity Enzymatic activity on receptor’s tyrosine

kinase and on separate cytoplasmic kinases (JAK kinases)bound to the receptor

Receptor and JAK kinase: function as a unit Messenger receptor activation of JAK

kinase phoshorylation of CHONs transcription factors synthesis of new CHONs that mediate cell’s response

Signal Transduction Pathways Receptors that interact with G proteins

Largest group of receptors G-proteins on the cytoplasm is bound to the

receptors Messenger receptor conformational

change 1 of 3 subunits of G-proteins link with plasma membrane effector proteins sequence of events cell’s response

G-proteins: serve as a switch to couple a receptor with an ion channel or an enzyme in plasma membrane

Signal Transduction Pathway Effector Protein Enzymes:

Adenylyl cyclase and Cyclic AMP Phospholipase C, diacylglycerol, and

Inositol Triphosphate

Signal Transduction Pathway Adenylyl cyclase and cyclic AMP

Messenger receptor activation of G protein activation of Adenylyl Cyclase conversion of ATP cAMP (2nd messenger) sequence of events cell’s response

Phosphodiesterase: enzyme that breaks down cAMP to non cyclic AMP, thus termination of its action

cAMP activation cAMP dependent protein kinase (Protein-kinase A) phosphorylation of proteins cell response

Amplification: 1 active adenylyl cyclase catalyzation of > 100 cAMP molecules

cAMP dependent protein kinase can phosphorylate large number of different proteins exert multiple actions on a cell

cAMP dependent protein kinase may inhibit other enzymes

Signal Transduction Pathway

Signal Transduction Pathways

Signal Transduction Pathways

Signal Transduction Pathways Phospholipase C, Diacylglycerol, and

Inositol Triphosphate Gq phospholipase C breakdown of PIP2

DAG and IP3 different sequence cascade cell response

DAG activates protein kinase C phosphorylation of many proteins cell response

IP3 enters cytosol binds wiith Ca++ channels in Endoplasmic reticulum opening of Ca++ channels Ca++ diffuses from ER to cytosol increase cytostolic CA++ sequence of events cell response

Signal Transduction Pathways

Signal Transduction Pathways Control of ions by G

Proteins Direct G-protein gating

(fig 7-13d) G-protein interacts

directly with ion channels in PM

All events occur in the plasma membrane

No 2nd messengers involved

Indirect G-protein gating (fig 7-17) Utilizes a 2nd messenger

Signal Transduction Pathways Ca++ ion as a 2nd

messenger Ca++ is maintained

extremely low in cytosol Large electrochemical

gradient favoring diffusion of Ca++ via channels in both PM and ER

Stimulus: change cytostolic Ca++ levels Active transport systems Ion channels

Ca++ channels openingChemical stimuliElectrical gradient

Ca++ (2nd messenger) bind channels in ER opening of channels release of Ca++ from ER ( calcium-induced calcium release)

2nd messenger IP3 Ca++

Signal Transduction Pathways Ca++ ions as 2nd

messenger Ca++ can bind with various

CHONs Ca++ binding alters CHON

conformation and activates their function Calmodulin + Ca++

change in shape activation/inhibition of protein kinases

Calmodulin –dependent protein kinase activation/inibition phosphorylation activation/inibition of CHONs cell response

Signal Transuction Pathways

Signal Transduction Pathways Receptors and Gene

Transcription Plasma membrane

receptors: transduction pathways activate Intracellular transcription factors using 2nd messengers

Primary Response Genes: Genes with transcription

factors activated by first messenger

Proteins encoded by PRGs may itself be a transcription factor for another gene

Signal Transduction Pathways Cessation of activity in signal transduction

Key event: cessation of receptor activation Decrease in the concentration of the first messenger

molecules in the region of the receptor Metabolism by enzymes in the vicinity Uptake by adjacent cells Diffusion away

Chemical alteration of the receptor (usually by phosphorylation)

Lower affinity for the 1st messenger Release of the messenger

Removal of plasma membrane receptor and its endocytosis

Signal Transduction Pathways