Physiologic Concepts and Cell Signaling

Pharmacology

What is homeostasis?

The maintenance of a stable environment that requires energy, involving positive and negative feedback, and feedforward loops.

How do equilibrium and steady state differ?

In equilibrium, there is no net transfer of matter or energy from one compartment to another, while steady state may require energy to maintain but does not change with time.

What are the key components of feedback systems?

Receptor (monitors variable), Control Center (establishes set point), Effector (changes variable). Examples include blood pressure, body temperature, and blood glucose.

What is the primary purpose of feedforward control? Provide an example.

Feedforward control anticipates changes in regulated variables before they are sensed. An example is an increased heart rate before exercise.

How does positive feedback differ from feedforward control? Provide an example of positive feedback.

Positive feedback continues to change in response to a stimulus, while feedforward control changes preventively. An example of positive feedback is childbirth.

What are key components of the cell membrane that impact its physiologic function?

The cell membrane consists of a bilipid layer, is selectively permeable, and contains distinctive proteins that allow movement in and out.

What is the role of cell membrane permeability in normal physiology?

It maintains the concentration gradient for action potentials, allowing gases and small lipophilic molecules to freely diffuse, while larger molecules require a carrier protein or channel.

What are the key functions of transmembrane proteins in normal physiology?

Transmembrane proteins function as transporters, anchors, receptors, and enzymes.

What are three common mechanisms for movement of substances across a cell membrane?

Phagocytosis, Endocytosis, and Exocytosis.

How does diffusion differ from active transport?

Diffusion occurs down a concentration gradient, while active transport requires energy and a carrier to move substances against the concentration gradient.

What is the most important physiologic variable for simple diffusion? Why?

The concentration gradient of the substance across the membrane determines if it will require a channel or pore or if it can move freely.

How is facilitated diffusion similar to and different from simple diffusion? Provide an example of facilitated diffusion.

Facilitated diffusion requires a carrier protein and has a Vmax, while simple diffusion does not require ATP and has no Vmax. An example is glucose transporters.

What are key features of membrane ion channels?

Membrane ion channels are specific to substances (ions), can be ungated (leak channels) or gated, and open due to voltage changes or other stimuli.

What drives the net movement of a substance through a channel?

Simple diffusion occurs down the concentration gradient.

What are the key differences between primary and secondary active transport?

Primary active transport uses ATP directly against the concentration gradient, while secondary active transport uses the concentration gradient of another molecule indirectly.

What is the Na+/K+ ATPase pump and its role?

It is a primary active transport carrier protein present on all cells that regulates osmotic balance and maintains the Na+/K+ gradient.

How are facilitated diffusion and active transport similar?

Both involve carrier proteins and have a Vmax.

What are the energetics of secondary active transport?

Secondary active transport utilizes the energy from the concentration gradient of another molecule to drive transport.

What are the two basic types of transporters in secondary active transport?

Symporters (move two substances in the same direction) and antiporters (move two substances in opposite directions).

What is the role of a transport carrier protein in active transport?

It uses the energy from one molecule (usually sodium) moving down its gradient to move another molecule against its concentration gradient.

What are the two types of transporters based on the direction of molecule movement?

Co-transporter (Symporter) moves molecules in the same direction, while Counter-transporter (Antiporter) moves them in opposite directions.

How do pumps facilitate the movement of substances from the luminal to basolateral side of an epithelial cell?

They typically involve a combination of primary (Na+/K+ ATPase pump) and secondary active transport pumps.

What is osmosis?

The diffusion of water across a semi-permeable membrane.

What is osmotic pressure?

The pull from the gradient; higher concentration results in higher osmotic pressure.

What physiological roles does osmotic pressure play?

It maintains cell volume and intravascular volume, preventing fluid leakage from blood vessels.

How does tonicity differ from osmotic pressure?

Tonicity is based on solutes that are impermeable to the cell membrane, while osmotic pressure is related to the concentration gradient.

What are the three classifications of tonicity?

Isotonic (similar), Hypertonic (higher), Hypotonic (lower) compared to extracellular fluid.

What components maintain the resting membrane potential in most cells?

Ungated sodium channels, ungated potassium channels, and leak channels for Na+/K+.

How is water primarily exchanged across cell membranes?

Through aquaporin channels.

Which ions are in higher concentration in the extracellular space?

Na+, Mg2+, HCO3-, Cl-.

Which ions are in higher concentration in the intracellular space?

K+, H+, SO42-, PO3-, proteins.

What is membrane potential?

The charge difference across the membrane.

What determines the membrane potential for a particular ion?

The ratio of the concentration of the ion across the membrane.

What is the typical membrane potential for most cells?

-70 to -90 mV, with the inside of the cell being more negative.

Which ion is most important in determining the membrane potential?

Potassium, as the resting potential is closest to its equilibrium.

What are the three types of local communication between cells?

Gap junctions, Autocrine signaling, and Paracrine signaling.

Provide an example of Gap junction communication.

Communication in the small intestine.

Provide an example of Autocrine communication.

Platelet signaling.

Provide an example of Paracrine communication.

Nitric oxide signaling in blood vessels.

What are the three types of remote communication between cells?

Nervous, Endocrine, and Neuroendocrine communication.

Provide an example of Nervous communication.

Communication from the brain directly to cells.

Provide an example of Endocrine communication.

Insulin regulating target cells.

What is cellular signaling?

Tightly regulated pathways that allow transduction of a signal within a target cell.

What are the key components of cellular signaling?

First messenger (ligand), receptors, transducers/effectors, and second messengers.

What are some key transducers in cellular signaling?

G protein-coupled receptors, ion channels, and tyrosine kinase receptors.

What are the key effector targets of G Protein-coupled receptors?

Ion channels and membrane-bound proteins.

What are the two key effector molecules in G Protein-coupled receptor signaling?

Adenylyl cyclase and phospholipase C.

What activates the G protein in G Protein-coupled receptors?

Binding of the first messenger (ligand) to the receptor.

Which G protein subunit binds to adenylyl cyclase?

The alpha subunit.

What results from the binding of the G protein to adenylyl cyclase?

The conversion of ATP to cyclic AMP (cAMP), a second messenger.

What is the role of the alpha subunit in GTP binding?

The alpha subunit converts ATP to cyclic AMP (cAMP).

What happens when cAMP is formed in G Protein-coupled receptors?

cAMP activates Protein Kinase A, which phosphorylates proteins causing biological effects such as enzyme activation, ion channel modulation, and activation of gene transcription factors.

How is cAMP removed from the cell?

cAMP is degraded to 5' AMP by phosphodiesterase.

What are the key classes of G proteins and their effects?

s - stimulates adenylyl cyclase; i - inhibits adenylyl cyclase; q - activates phospholipase; o - closes Ca2+ channels.

What other pathways may be activated by G Protein-coupled receptors?

Phospholipase A2 (PLA2) which cleaves phospholipids to form arachidonic acid.

What are the mechanisms by which gated ion channels can open and close?

Gated ion channels can open and close through ligand binding, changes in membrane potential, and mechanical or thermal disruption.

What are the key features of ungated (leakage) channels?

Ungated channels are always open, primarily consist of potassium and chloride channels, determine resting membrane potential (RMP), and are specific to one ion.

What are the similarities and differences between ligand-gated and voltage-gated channels?

Similarities: specific to a particular ion, ions move in both directions, passive diffusion down concentration gradient. Differences: ligand-gated channels respond to specific stimuli and can remain open as long as the stimulus is bound; voltage-gated channels open at a certain threshold and have predetermined open/close durations.

What is the key physiological role of tyrosine kinase receptors?

Tyrosine kinase receptors have intrinsic ability to phosphorylate and are regulated by hormones and growth factors, leading to increased gene transcription, growth, and cell differentiation.

What are some examples of important tyrosine kinase receptors?

Examples include EGF receptor, Insulin receptor, and cytokine receptor.

What are some effectors of tyrosine kinase receptors?

Effectors include Phospholipase C (PLC), Phospholipase A2 (PLA2), and Phosphatidylinositol-3 or 4 kinase (PI3 kinase or PI4 kinase).

What are some key second messengers in cell signaling?

Key second messengers include hydrophilic (cAMP, cGMP, Ca2+), hydrophobic (membrane-associated), and gases (NO, CO).

What are the purposes of signaling cascades?

Signaling cascades amplify small stimuli, diversify responses in different cells, allow multiple actions within a cell, and provide tight control over cellular processes.

What are the key effects of Phospholipase C activation?

Phospholipase C converts phosphatidylinositol 4,5-bisphosphate into diacylglycerol (DAG) which activates protein kinase C, and inositol triphosphate (IP3) which stimulates intracellular calcium release.

What mechanisms can increase intracellular calcium levels?

Increased intracellular calcium can occur through voltage-gated channels, PKA, PKC, IP3, and ryanodine receptors.

What are some roles of intracellular calcium release?

Roles include binding effector molecules like PKC and calmodulin to activate downstream targets, neurotransmitter release, muscle contraction, and hormone release (e.g., insulin).

What may result from altered intracellular calcium homeostasis?

Altered calcium homeostasis can lead to enzyme activation, cell membrane damage, cytoskeleton damage, ATP depletion, DNA destruction, and irreversible cell injury.

What signaling system do hormone receptors primarily target?

Hormone receptors primarily target the G protein signaling system.

What is the primary target for steroid hormones?

The primary target for steroid hormones is the receptor in the nucleus, such as cortisol.

What are the key structures of a neuron and their overall purpose?

Key structures of a neuron include the cell body (soma), dendrites (receive signals), axon (transmits signals), and synaptic terminals (release neurotransmitters).

What is the function of dendrites in a neuron?

Dendrites receive input from other cells.

What is the role of the soma (cell body) in a neuron?

The soma contains the nucleus and is the site of neurotransmitter synthesis.

What occurs at the axon hillock?

It is the junction where the soma meets the axon, and the threshold must be reached for an action potential to be generated.

What is the primary function of the axon?

The axon transmits action potentials away from the soma and contains specialized transport proteins.

What happens at the axon terminal?

The axon terminal is the site of synapse and neurotransmitter release.

What channels are involved in reaching the resting membrane potential?

Ungated potassium (leak) channels maintain the resting membrane potential.

What channels are involved in depolarization during an action potential?

Voltage-gated sodium channels open, allowing sodium to enter the cell.

What is hyperpolarization and what channels can cause it?

Hyperpolarization is when the potential becomes more negative, caused by voltage-gated potassium channels remaining open or chloride channels opening.

How does hyperkalemia affect action potentials?

Hyperkalemia increases the rate of depolarization due to elevated K+ levels.

What is the effect of hypokalemia on action potentials?

Hypokalemia decreases the rate of depolarization and can cause hyperpolarization due to decreased K+ levels.

How do changes in serum sodium impact action potentials?

Changes in serum sodium have little effect because sodium channels remain closed until activated.

What is the effect of calcium on action potentials?

A decrease in Ca2+ opens gates leading to depolarization, while an increase in Ca2+ closes gates leading to hyperpolarization.

What is the sequence of channel changes during an action potential?

1. Upstroke (depolarization) - voltage-gated sodium channels open. 2. Inactivation of sodium channels. 3. Downstroke (repolarization) - voltage-gated potassium channels open.

What are some of the key characteristics of action potentials?

Unidirectional; All or none once threshold reached; Constant amplitude (no summation); Conduction down an axon is always the same, but varies based upon myelination and fiber diameter.

Myelinated fibers are faster than nonmyelinated fibers which allow the action potential to skip down the axon at a faster speed.

What are some of the key functions of action potentials?

Transmit information into, out of, and within the CNS; Transmit in sensory input and motor function out; Frequency of APs encodes the information; Allows rapid transmission over a distance.

What is the site where action potentials communicate between cells? What signals may result?

Synapse – synaptic junction (presynaptic and postsynaptic cells); Electrical (muscle contraction) or Chemical (release of another mediator)

What are the key steps involved in a signal at a chemical synapse?

Action potential (voltage-gated sodium channels) move down axon; Open voltage-gated calcium channels in the presynaptic terminal; Results in fusion and exocytosis of vesicles containing neurotransmitter; Diffuse across synaptic cleft; Bind to receptors on postsynaptic membrane to elicit an effect.

What are the key calcium regulatory proteins the regulate exocytosis at the presynaptic membrane?

v-snares and t-snares – interact to hold the vesicles at the terminal;

synaptogamin – calcium sensor that causes the docking and release of the vesicles

What are key fatigue mechanisms for synaptic transmission?

Exhaustion of neurotransmitters, inactivation of postsynaptic receptors, development of abnormal ion concentration inside postsynaptic cells

What are some factors that impact transmission?

Increase transmission: alkalosis, caffeine, theophylline, theobromine

Decrease transmission: acidosis, hypoxia, anesthetics (change threshold).

What are the three key steps in neuronal communication via a neurotransmitter?

Release from the presynapse; Receptor binding at the postsynapse with effect; removal (diffusion from site, reuptake of the neurotransmitter; metabolism of the neurotransmitter.

What are the key mechanisms of inhibitory neurotransmitters? What are the key mechanisms of excitatory neurotransmitters?

Inhibitory: Open a chloride channel (direct), Open a potassium channel (indirect), Close a calcium channel (indirect)

Stimulatory: Open a sodium or calcium channel (direct), Close a potassium channel (indirect), Open a calcium channel (indirect).

How do presynaptic and postsynaptic receptors differ in function?

Presynaptic – usually regulate the amount of neurotransmitter released from the synapse

Postsynaptic – usually effector

What is the substrate for acetylcholine (Ach) synthesis?

Acetyl-CoA from glucose; Metabolized by acetylcholinesterase

How is acetylcholine (Ach) removed?

Choline reuptake for reuse

What receptors does acetylcholine (Ach) act upon?

Nicotinic and Muscarinic receptors

What are the key types of nicotinic receptors and what types of neurotransmitter are they?

N₁ (neuromuscular junctions) and N2 (autonomic ganglia) ionotropic receptors

What are the key types of muscarinic receptors and what types of neurotransmitter are they?

M_1,3,5 via G_q (activates) PLC

M_2,4 via G_i (inhibits PKA) (GPC)

What is the substrate for catecholaminergic synthesis?

Tyrosine

What is the rate-limiting enzyme in catecholaminergic synthesis and how is it regulated?

Tyrosine hydroxylase – increased synthesis via cAMP kinase or increase TH production