Chapter 3 Membrane Physiology Sections

Chapter 3 Membrane Physiology Sections 3.4-3.5

3.4 Intercellular Communication and Signal Transduction
Direct intercellular communication Gap junctions Transient direct linkup of surface markers Nanotubes Indirect intercellular communication Intercellular chemical messengers Synthesized by specialized cells to serve a designated purpose Bind with specific receptors on target cells 2

Small molecules and ions
FIGURE 3-16 Types of intercellular communication. Gap junctions (a), transient/direct linkup of cells (b), and nanotubes (c) are means of direct communication between cells. Paracrines (d), neurotransmitters (e), hormones (f), neurohormones (g), and pheromones (h) are all extracellular chemical messengers that accomplish indirect communication between cells. These chemical messengers differ in their source and the distance they travel to reach their target cells. (a) Gap junctions Figure 3-16a p92

(b) Transient direct linkup of cells’ surface markers
FIGURE 3-16 Types of intercellular communication. Gap junctions (a), transient/direct linkup of cells (b), and nanotubes (c) are means of direct communication between cells. Paracrines (d), neurotransmitters (e), hormones (f), neurohormones (g), and pheromones (h) are all extracellular chemical messengers that accomplish indirect communication between cells. These chemical messengers differ in their source and the distance they travel to reach their target cells. (b) Transient direct linkup of cells’ surface markers Figure 3-16b p92

Plasma membrane component Small cytoplasmic molecule
Direction of transfer F-actin FIGURE 3-16 Types of intercellular communication. Gap junctions (a), transient/direct linkup of cells (b), and nanotubes (c) are means of direct communication between cells. Paracrines (d), neurotransmitters (e), hormones (f), neurohormones (g), and pheromones (h) are all extracellular chemical messengers that accomplish indirect communication between cells. These chemical messengers differ in their source and the distance they travel to reach their target cells. Organelle (c) Nanotubes Figure 3-16c p92

Categories of chemical messengers Paracrines -- local chemical messengers whose effect is exerted only on neighboring cells Neurotransmitters -- used by neurons which communicate directly with the cells they innervate Hormones -- long-range chemical messengers that are secreted into the circulation by endocrine glands 7

Categories of chemical messengers Neurohormones -- hormones released into the circulation by neurosecretory neurons Pheromones -- chemical signals released into the environment to reach sensory cells of other animals Cytokines -- regulatory peptides made by almost any cell, generally involved in development and immunity 8

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(d) Paracrine secretion
Secreting cell Local target cell Paracrine FIGURE 3-16 Types of intercellular communication. Gap junctions (a), transient/direct linkup of cells (b), and nanotubes (c) are means of direct communication between cells. Paracrines (d), neurotransmitters (e), hormones (f), neurohormones (g), and pheromones (h) are all extracellular chemical messengers that accomplish indirect communication between cells. These chemical messengers differ in their source and the distance they travel to reach their target cells. (d) Paracrine secretion Figure 3-16d p92

(e) Neurotransmitter secretion
Local target cell Electrical signal Secreting cell (neuron) FIGURE 3-16 Types of intercellular communication. Gap junctions (a), transient/direct linkup of cells (b), and nanotubes (c) are means of direct communication between cells. Paracrines (d), neurotransmitters (e), hormones (f), neurohormones (g), and pheromones (h) are all extracellular chemical messengers that accomplish indirect communication between cells. These chemical messengers differ in their source and the distance they travel to reach their target cells. Neurotransmitter (e) Neurotransmitter secretion Figure 3-16e p92

(f) Hormonal secretion
Blood Secreting cell (endocrine cell) Hormone Distant target cell Nontarget cell (no receptors) FIGURE 3-16 Types of intercellular communication. Gap junctions (a), transient/direct linkup of cells (b), and nanotubes (c) are means of direct communication between cells. Paracrines (d), neurotransmitters (e), hormones (f), neurohormones (g), and pheromones (h) are all extracellular chemical messengers that accomplish indirect communication between cells. These chemical messengers differ in their source and the distance they travel to reach their target cells. (f) Hormonal secretion Figure 3-16f p92

(g) Neurohormone secretion
Blood Electrical signal Secreting cell (neuron) Distant target cell Nontarget cell (no receptors) FIGURE 3-16 Types of intercellular communication. Gap junctions (a), transient/direct linkup of cells (b), and nanotubes (c) are means of direct communication between cells. Paracrines (d), neurotransmitters (e), hormones (f), neurohormones (g), and pheromones (h) are all extracellular chemical messengers that accomplish indirect communication between cells. These chemical messengers differ in their source and the distance they travel to reach their target cells. (g) Neurohormone secretion Figure 3-16g p92

Gland FIGURE 3-16 Types of intercellular communication. Gap junctions (a), transient/direct linkup of cells (b), and nanotubes (c) are means of direct communication between cells. Paracrines (d), neurotransmitters (e), hormones (f), neurohormones (g), and pheromones (h) are all extracellular chemical messengers that accomplish indirect communication between cells. These chemical messengers differ in their source and the distance they travel to reach their target cells. (h) Pheromones Figure 3-16h p92 14

Extracellular chemical messengers bind with receptors to trigger a biochemical chain of events inside the target cell Signal transduction is the process by which incoming signals are conveyed to the target cell’s interior for execution 15

Lipophilic extracellular messengers Pass through the target cell’s plasma membrane to bind to intracellular receptors Produce second messenger, cyclic GMP (e.g. nitric oxide) or Alter gene transcription (e.g. thyroid and steroid hormones) 16

Lipophobic extracellular messengers Cannot pass through the target cell’s plasma membrane; bind with surface membrane receptors Open or close specific membrane channels to regulate ion movement or Activate an enzyme that phosphorylates a cell protein or Transfer the signal to an intracellular second messenger 17

Opening and closing of membrane receptor-channels Chemically gated (ligand gated) Respond to binding of an extracellular chemical messenger to a specific membrane receptor Voltage gated Respond to changes in the electrical current in the plasma membrane Mechanically gated Respond to stretching or other mechanical deformation of the channel 18

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1) Extracellular messenger binds to receptor.
Ion 1) Extracellular messenger binds to receptor. Receptor- channel Extracellular messenger 2) Binding of messenger leads to opening of channel. 3) Ions enter. Ion entry FIGURE 3-17 Types of receptors according to mode of action. (a) A receptor-channel opens when an extracellular messenger binds to it. The resultant ion entry ultimately leads to the cellular response. (b) An enzyme site on the cytoplasmic side of a receptor-enzyme is activated when an extracellular messenger binds to the side facing outside the cell. The activated receptor-bound enzyme ultimately leads to the cellular response. (c) Binding of an extracellular (first) messenger to the extracellular side of a G-protein coupled receptor activates a membrane-bound effector protein by means of a G-protein intermediary. The effector protein produces an intracellular second messenger, which ultimately leads to the cellular response. (perhaps through multiple steps) 4) Ion entry brings about desired result. Cellular response (a) Chemically gated receptor-channel Figure 3-17a p95 20

1) Extracellular messenger binds to receptor.
Receptor- enzyme Active protein kinase site 2) Binding of messenger leads to activation of protein kinase enzyme site. (perhaps through multiple steps) 3) Protein kinase activates designated protein. FIGURE 3-17 Types of receptors according to mode of action. (a) A receptor-channel opens when an extracellular messenger binds to it. The resultant ion entry ultimately leads to the cellular response. (b) An enzyme site on the cytoplasmic side of a receptor-enzyme is activated when an extracellular messenger binds to the side facing outside the cell. The activated receptor-bound enzyme ultimately leads to the cellular response. (c) Binding of an extracellular (first) messenger to the extracellular side of a G-protein coupled receptor activates a membrane-bound eff ector protein by means of a G-protein intermediary. The effector protein produces an intracellular second messenger, which ultimately leads to the cellular response. Active designated protein 4) Active designated protein brings about desired response. Cellular response (b) Receptor-enzyme Figure 3-17b p95 21

1) Extracellular (first) messenger binds to receptor.
G-protein coupled receptor ECF Plasma membrane ICF Effector protein 2) Receptor activates G protein. Active G protein 3) G protein activates effector protein. 4) Effector protein produces second messenger. Second messenger 5) Second messenger activates protein kinase. Active protein kinase (perhaps through multiple steps) FIGURE 3-17 Types of receptors according to mode of action. (a) A receptor-channel opens when an extracellular messenger binds to it. The resultant ion entry ultimately leads to the cellular response. (b) An enzyme site on the cytoplasmic side of a receptor-enzyme is activated when an extracellular messenger binds to the side facing outside the cell. The activated receptor-bound enzyme ultimately leads to the cellular response. (c) Binding of an extracellular (first) messenger to the extracellular side of a G-protein coupled receptor activates a membrane-bound effector protein by means of a G-protein intermediary. The effector protein produces an intracellular second messenger, which ultimately leads to the cellular response. 6) Protein kinase activates designated protein. Active designated protein 7) Active designated protein brings about desired response. Cellular response (c) G-protein coupled receptor Figure 3-17c p95 22

Phosphorylating enzymes Protein kinase phosphorylates a target cell protein Phosphorylated protein changes shape and function (is activated) Tyrosine kinase (e.g. insulin receptor) phosphorylates its own tyrosine residues (autophosphorylation). Activated protein kinase sites phosphorylate cytoplasmic proteins to lead to the cellular response 23

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2) Protein kinase site self-phosphorylates receptor’s tyrosines.
Extracellular messengers (signal molecules) 1) Two extracellular messengers bind to two receptors and receptors pair, activating receptor’s protein kinase site. Tyrosine kinase receptor- enzyme ECF Plasma membrane ICF 2) Protein kinase site self-phosphorylates receptor’s tyrosines. Protein kinase sites (active) 3) Inactive designated protein binds to receptor, which phosphorylates protein, activating it. FIGURE 3-18 Tyrosine kinase pathway. Two extracellularmessengers bindto two receptorsand receptors pair,activating receptor’sprotein kinase site. Protein kinase site self-phosphorylatesreceptor’s tyrosines. Inactive designated protein binds to receptor, which phosphorylatesprotein, activating it. Active designated protein brings about desired response. Inactive designated protein (changes shape and function) Active designated protein 4) Active designated protein brings about desired response. Cellular response Figure 3-18 p96 25

G protein-coupled membrane receptors (GPCRs) Inactive G protein on inner surface of plasma membrane contains α, β and γ subunits with a GDP bound to the α subunit When hormone binds with its receptor, the receptor attaches to G protein, releasing GDP and attaching GTP to the α subunit Activated α subunit links with an effector protein in the membrane and alters its activity 300 different receptors use the G protein mechanism 26

Cyclic AMP second-messenger GPCR pathway Binding of hormone (first messenger) to its receptor activates a G protein Activated α subunit links with adenylyl cyclase in the membrane Activated adenylyl cyclase converts intracellular ATP to cyclic AMP Cyclic AMP activates protein kinase A Protein kinase A phosphorylates intracellular proteins, leading to the cellular response 27

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1 2 3 4 5 Extracellular (first) messenger (Activates)
G protein intermediary ECF Plasma membrane Adenylyl cyclase (effector protein) ICF G-protein coupled receptor (Activates) Second messenger Binding of extracellular Messenger to receptor Activates a G protein, the α subunit of which shuttles to and activates adenylyl cyclase. 1 Adenylyl cyclase converts ATP to cAMP 2 cAMP activates protein kinase A. 3 Inactive protein kinase A Active protein kinase A FIGURE 3-19 Mechanism of action of hydrophilic hormones via activation of the cyclic AMP second-messenger pathway. Protein kinase A phosphorylates inactive designated protein, activating it. 4 Inactive designated protein (changes shape and function) Active designated protein Active designated protein brings about desired response. 5 Key Phosphate Cellular response Figure 3-19 p97

Diacylglycerol-inositol triphosphate-Ca2+ second-messenger pathway Binding of hormone (first messenger) to its receptor activates a G protein Activated α subunit activates phopholipase C on inner surface of membrane Activated phospholipase C converts phospatidyl-inositol bisphosphate (PIP2) to diacylglycerol (DAG) and inositol trisphosphate (IP3) 30

Diacylglycerol-inositol triphosphate-Ca2+ second-messenger pathway IP3 diffuses into cytosol and mobilizes intracellular Ca2+ stores Ca2+ serves as second messenger leading to cellular response DAG activates protein kinase C Protein kinase C phosphorylates intracellular proteins leading to the cellular response 31

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Second messenger systems Shared by many cell types Multiple steps lead to amplification of initial signal Receptors are subject to regulation Downregulation or upregulation of receptor number Drugs and toxins alter communication pathways Antagonists block a step in the pathway Agonists activate a step in the pathway 33

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ANIMATION: Signal transduction
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3.5 Membrane Potential Membrane potential is the separation of charges across the plasma membrane Measured in millivolts Attractive force causes separated positive and negative charges to accumulate along the inner and outer surfaces of the membrane All living cells have a membrane potential with excess of negative charges on the inside Cells of excitable tissues (nerve and muscle) have the ability to produce rapid, transient changes in membrane potential 36

3.5 Membrane Potential 37

(a) Membrane has no potential
FIGURE 3-22 Determination of membrane potential by unequal distribution of positive and negative charges across the membrane. (a) When the positive and negative charges are equally balanced on each side of the membrane, no membrane potential exists. (b) When opposite charges are separated across the membrane, membrane potential exists. (c) The unbalanced charges responsible for the potential accumulate in a thin layer along opposite surfaces of the membrane. (d) The vast majority of the ﬂuid in the ECF and ICF is electrically neutral. The unbalanced charges accumulate along the plasma membrane. (10+, 10–) (10+, 10–) (a) Membrane has no potential Figure 3-22a p103

(b) Membrane has potential
FIGURE 3-22 Determination of membrane potential by unequal distribution of positive and negative charges across the membrane. (a) When the positive and negative charges are equally balanced on each side of the membrane, no membrane potential exists. (b) When opposite charges are separated across the membrane, membrane potential exists. (c) The unbalanced charges responsible for the potential accumulate in a thin layer along opposite surfaces of the membrane. (d) The vast majority of the ﬂuid in the ECF and ICF is electrically neutral. The unbalanced charges accumulate along the plasma membrane. (15+, 10–) (5+, 10–) (b) Membrane has potential Figure 3-22b p103

(c) Separated charges responsible for potential
Remainder of fluid electrically neutral Separated charges Remainder of fluid electrically neutral FIGURE 3-22 Determination of membrane potential by unequal distribution of positive and negative charges across the membrane. (a) When the positive and negative charges are equally balanced on each side of the membrane, no membrane potential exists. (b) When opposite charges are separated across the membrane, membrane potential exists. (c) The unbalanced charges responsible for the potential accumulate in a thin layer along opposite surfaces of the membrane. (d) The vast majority of the ﬂuid in the ECF and ICF is electrically neutral. The unbalanced charges accumulate along the plasma membrane. (c) Separated charges responsible for potential Figure 3-22c p103

d) Separated charges forming a layer along plasma membrane
FIGURE 3-22 Determination of membrane potential by unequal distribution of positive and negative charges across the membrane. (a) When the positive and negative charges are equally balanced on each side of the membrane, no membrane potential exists. (b) When opposite charges are separated across the membrane, membrane potential exists. (c) The unbalanced charges responsible for the potential accumulate in a thin layer along opposite surfaces of the membrane. (d) The vast majority of the ﬂuid in the ECF and ICF is electrically neutral. The unbalanced charges accumulate along the plasma membrane. Plasma membrane d) Separated charges forming a layer along plasma membrane Figure 3-22d p103

3.5 Membrane Potential Resting membrane potential is primarily due to differences in the distribution and permeability of key ions Na+ is greater in ECF; K+ is greater in ICF Concentration differences are maintained by Na+-K+ pump Different solubilities in cell water and affinity for cell proteins Large, negatively charged proteins (A-) are concentrated in ICF 42

3.5 Membrane Potential Resting membrane potential is primarily due to differences in the distribution and permeability of key ions Na+-K+ pump transports 3 Na+ out for every 2 K+ in Membrane has more K+ leak channels than Na+ leak channels Membrane is times more permeable to K+ than to Na+ 43

3.5 Membrane Potential Equilibrium potential
The equilibrium potential of an ion is the membrane potential at which there is no net movement of the ion across the membrane. Concentration gradient is balanced by opposing electrical gradient Nernst equation for equilibrium potential of an ion (Eion): Eion = 61 log Co z Ci 44

Plasma membrane ECF ICF Concentration gradient for K+ Electrical
FIGURE 3-23 Equilibrium potential for K+. The concentration gradient for K+ tends to move this ion out of the cell. The outside of the cell becomes more positive as K+ ions move to the outside down their concentration gradient. The membrane is impermeable to the large intracellular protein anion (A–). The inside of the cell becomes more negative as K+ ions move out, leaving behind A–. The resulting electrical gradient tends to move K+ into the cell. No further net movement of K+ occurs when the inward electrical gradient exactly counterbalances the outward concentration gradient. The membrane potential at this equilibrium point is the equilibrium potential for K+ (EK+) at –90 mV. EK+ = –90 mV Figure 3-23 p105

ECF anions, Plasma membrane ECF ICF Concentration gradient for Na+
Electrical gradient for Na+ FIGURE Equilibrium potential for Na+. The concentration gradient for Na+ tends to move this ion into the cell. The inside of the cell becomes more positive as Na+ ions move to the inside down their concentration gradient. The outside becomes more negative as Na+ ions move in, leaving behind in the ECF unbalanced negatively charged ions, mostly Cl–. The resulting electrical gradient tends to move Na+ out of the cell. No further net movement of Na+ occurs when the outward electrical gradient exactly counterbalances the inward concentration gradient. The membrane potential at this equilibrium point is the equilibrium potential for Na+ (ENa+) at +60 mV. ECF anions, mostly ENa+ = +60 mV Figure 3-24 p106

3.5 Membrane Potential Equilibrium potential EK = -90 mV ENa = 61 mV
The greater the permeability of the plasma membrane for a given ion, the greater the tendency for that ion to drive the membrane potential toward the ion’s own equilibrium potential. The membrane is more permeable to K+ than to Na+, so membrane potential is closer to the K+ equilibrium potential 48

Resting membrane potential = –70 mV
Plasma membrane Relatively large net diffusion of K+ outward establishes an EK+ of –90 mV ECF ICF No diffusion of A– across membrane Relatively small net diffusion of Na+ inward neutralizes some of the potential created by K+ alone FIGURE 3-25 Eﬀect of concurrent K+ and Na+ movement on establishing the resting membrane potential. The Na+/K+ pump actively transports Na+ out of and K+ into the cell, keeping the concentration of Na+ high in the ECF and the concentration of K+ high in the ICF. Given the concentration gradients that exist across the plasma membrane, K+ tends to drive membrane potential to the equilibrium potential for K+ (–90 mV), whereas Na+ tends to drive membrane potential to the equilibrium potential for Na+ (+60 mV). However, K+ exerts the dominant effect on resting membrane potential because the membrane is more permeable to K+. As a result, resting potential (–70 mV) is much closer to EK+ than to ENa+. During the establishment of resting potential, the relatively large net diffusion of K+ outward does not produce a potential of –90 mV because the resting membrane is slightly permeable to Na+ and the relatively small net diffusion of Na+ inward neutralizes (in gray shading) some of the potential that would be created by K+ alone, bringing resting potential to 70 mV, slightly less than EK+. The negatively charged intracellular proteins (A–) that cannot cross the membrane remain unbalanced inside the cell during the net outward movement of the positively charged ions, so the inside of the cell is more negative than the outside. and associated Resting membrane potential = –70 mV Figure 3-25 p107

ANIMATION: Resting Potential

3.5 Membrane Potential The membrane potential (Vm) can be calculated using Goldman-Hodgkin-Katz equation. Takes into account the relative permeabilities and concentration gradients of all permeable ions (K+, Na+, Cl-) Vm = 61 log PK+ [K+]o + PNa+ [Na+]o PK+ [K+]i + PNa+ [Na+]i Resting membrane potential is -70 mV Cl- does not influence membrane potential in most cells because it is very near its equilibrium potential. 52

3.5 Membrane Potential Membrane potential is maintained at a steady state Passive leaks of K+ out of cell and Na+ into cell are balanced by the Na+-K+ pump 53

ECF Na+ /K+ pump (Passive) (Active) (Passive) (Active) Na+ channel
FIGURE 3-26 Counterbalance between passive Na+ and K+ leaks and the active Na+/K+ pump. At resting membrane potential, the passive leaks of Na+ and K+ down their electrochemical gradients are counterbalanced by the active Na+/K+ pump, so that there is no net movement of Na+ and K+, and the membrane potential remains constant. (Passive) (Active) Na+ channel K+ channel ICF Figure 3-26 p108 54

ANIMATION: Action Potential

ANIMATION: Measuring membrane potential

Chapter 3 Membrane Physiology Sections

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