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Comprehensive Notes: Physiology I — Bases of Regulation, Molecular Signaling, Plasma Membrane & Starling Forces

Weekly Course Schedule

  • Week 1 (8/25): Bases of Physiological Regulation — Dr. Godoy

  • Week 2 (9/1): Principles of Neurophysiology — Dr. Godoy

  • Week 3 (9/8): Muscle Physiology — Dr. Godoy

  • Week 4 (9/15): Neurophysiology — Dr. Godoy

  • Exam 1 (20%) — 9/16

  • Week 5 (9/22): Neurophysiology — Dr. Godoy

  • Week 6 (9/29): Neurophysiology — Dr. Godoy

  • Week 7 (10/6): Sensory Organs — Dr. Godoy

  • Week 8 (10/13): Blood Cells and Blood Coagulation — Dr. Godoy

  • Exam 2 (20%) — 10/14

  • Week 9 (10/20): Cardiovascular System — Dr. Tang

  • Week 10 (10/27): Cardiovascular System — Dr. Tang

  • Week 11 (11/3): Cardiovascular System — Dr. Tang

  • Week 12 (11/10): Cardiovascular System — Dr. Tang

  • Exam 3 (20%) — 11/11

  • Week 13 (11/17): Respiratory Physiology — Dr. Godoy

  • Week 14 (11/24): Respiratory Physiology — Dr. Godoy

  • Week 15 (12/1): Thermoregulation — Dr. Godoy

  • Week 16 (TBD): Final Exam (40%; cumulative)

Required Textbooks and Resources

  • Klein, Cunningham’s Textbook of Veterinary Physiology, 6th Ed. (Required)

  • Recommended books/online resources:

    • Sjaastadt, Sand, Hove. Physiology of Domestic Animals (ScanVetPress), 3rd Ed.

    • Reece. Duke’s Physiology of Domestic Animals, 13th Ed.

    • Hall. Guyton and Hall Textbook of Medical Physiology

    • Alberts. Molecular Biology of the Cell

    • NCBI PubMed, Evolve Elsevier (with access code), de Lahunta Vet

    • Cornell University, Neurology video collection

  • Textbooks/online resources (general): Scanvetpress, etc.

Teaching Philosophy & Course Context

  • The body constitutes one functional unit; organ systems are overlapping and strongly coupled.

  • Encourage questions and active engagement in learning.

  • Physiology concepts must be understood and explained, not memorized.

  • Emphasis on integration of material with >20 clinical correlations in the semester.

  • Commitment to hard work and constant improvement (class average last four years: ~85–90%).

  • Review questions and office time available for student support.

Course Administration & Ethics

  • Copyright and file sharing notice: Materials are protected by US copyright law. Do not share, distribute, or upload course materials outside the course without permission. Materials may be removed if considered a violation.

Part 1: Physiology I — Bases of Physiological Regulation (Part 1)

Learning Objectives (Part 1)

  • Define homeostasis and provide examples.

  • Explain the concept of cell compartmentation and provide examples.

  • Explain the relevance of proteins in physiology.

  • List factors that affect protein function.

Core Concepts

  • Homeostasis concepts include: energy requirement for maintaining stable internal conditions; integration with energy metabolism; signals, receptors, and effectors coordinate responses.

  • Homeostasis requires energy; concept of energy expenditure as part of regulatory processes.

  • Proteins are the basis of all physiological change (enzymes, transporters, receptors, structural proteins, signaling components).

  • Cells communicate via sophisticated signaling language; plasma membrane characteristics shape electrochemical gradients.

Homeostasis: Energy and Disease

  • Homeostasis is a self-regulating process to maintain core physiological conditions within narrow limits despite environmental changes.

  • Homeostatic imbalance can lead to disease, aging effects, genetic mutations, pathogen effects, or environmental factors.

  • Stimulus–response model can be positive or negative feedback.

  • Systems involved in homeostatic control include nervous and endocrine pathways; both can act to restore homeostasis.

Negative and Positive Feedback

  • Negative feedback: most common; senses change and activates mechanisms to reverse it.

  • Positive feedback: self-amplifying and less common; accelerates change in the same direction until signal cessation or other factors terminate it.

Energy, Metabolism, and the Cell

  • Homeostasis equals energy expenditure in coordinated responses to re-establish order.

  • Cells continuously utilize energy to maintain structure, growth, transport, and shape changes; energy metabolism must remain functional, or cells die.

  • Main energy source in the cell is ATP (Adenosine triphosphate).

  • Other energy-producing molecules:

    • ext{NADH} (nicotinamide adenine dinucleotide)

    • ext{FADH}_2 (flavin adenine dinucleotide)

Metabolic Pathways (Overview)

  • Major energy pathways include:

    • Glycolysis (glucose metabolism to pyruvate + ATP)

    • Pentose-phosphate pathway (PPP)

    • Tricarboxylic Acid Cycle (TCA, Krebs cycle)

    • Oxidative phosphorylation (Electron Transport Chain, OXPHOS)

    • β-oxidation (fatty acid oxidation)

  • Macromolecules and their roles:

    • Monosaccharides serve as energy sources.

    • Fatty acids form fatty acids, glycerol backbones (triacylglycerols, phospholipids).

    • Amino acids used for proteins and other metabolic needs.

    • Nucleotides used for nucleic acids and energy carriers (e.g., ATP, NADH).

    • Enzymes, cofactors, and messengers facilitate regulation and reactions.

Proteins Do Everything

  • Roles of proteins:

    • Catalysis (enzymes)

    • Reaction coupling (e.g., muscle contraction)

    • Transport (carriers)

    • Structural functions (cytoskeleton components)

    • Signaling (G-protein coupled receptors, nuclear receptors, etc.)

Protein Function and Active Sites

  • Protein function depends on substrate specificity, governed by active sites.

  • Active sites are pockets with specific amino acid side chains that bind substrates.

  • Example: synthesis of neurotransmitters from the amino acid tyrosine.

  • Allosteric regulation and conformational changes modulate activity.

Allosteric Changes & Post-Translational Modifications

  • Allosteric changes can be triggered by:

    • Ligand binding

    • Covalent modifications (e.g., phosphorylation, hydroxylation, glycosylation)

    • Voltage changes

    • Mechanical forces

Part 2: Molecular Bases of Physiological Regulation — Part 2

Learning Objectives (Part 2)

  • Explain the concept of cell signaling and its components.

  • Classify receptors by cellular location; provide examples.

  • Explain ionotropic receptor operation with examples.

  • Explain G-protein coupled receptor (GPCR) operation and second messengers.

  • Describe signaling mediated by lipid-soluble messengers and provide examples.

Cell Signaling: Overview

  • Cell signaling (cell communication) concerns how cells send/receive signals from their environment and other cells.

  • Analogy: a Rube Goldberg device illustrating the idea of cascading signaling (door opener analogy in Klein text).

  • Four forms of cell signaling:

    • CONTACT-DEPENDENT: signaling cell contacts target cell via membrane-bound signals.

    • PARACRINE: local mediator released by signaling cell acts on nearby target cells via membrane-bound or soluble mediators.

    • SYNAPTIC: neuron releases neurotransmitter across synapse to target cell.

    • ENDOCRINE: endocrine cells release hormones into bloodstream to distant targets.

Receptors and Ligands

  • A receptor is a protein that receives chemical signals.

  • A ligand is a molecule that binds to a receptor and initiates downstream signaling.

  • Receptors may be located on the cell surface or intracellularly, depending on ligand properties (hydrophilic vs hydrophobic).

  • Cell-signaling receptor locations:

    • Cell surface receptors (for hydrophilic ligands):

    • Ligand-gated ion channels (ionotropic receptors)

    • G-protein-coupled receptors (GPCRs; metabotropic receptors)

    • Enzyme-coupled receptors (receptor tyrosine kinases, RTKs)

    • Toll-like receptors

    • Intracellular receptors (for hydrophobic ligands):

    • Steroid hormone receptors (cytosol)

    • Vitamin D receptor (nuclear)

    • Thyroid hormone receptors (nuclear)

Ligand-Gated Ion Channels (Ionotropic Receptors)

  • Example: Nicotinic acetylcholine receptor.

  • Mechanism: ligand binding opens channel, allowing ions to flow, leading to depolarization and excitation.

  • Location: plasma membrane.

G-Protein-Coupled Receptors (GPCRs) — Metabotropic Receptors

  • Largest family of receptors in humans (~800; ~1000 in rodents).

  • About 50% of commercial drugs act on GPCRs directly/indirectly.

  • Involvement: almost all physiological processes (neurotransmitters like adrenaline, acetylcholine, dopamine; hormones like angiotensin, calcitonin, gastrin; olfactory stimuli; opioids).

  • Signaling mechanism in 3 steps:
    1) Ligand binds GPCR → GPCR activates the G-protein (on/off switch).
    2) Alpha subunit binds GTP and activates enzymes/ion channels to propagate signal interiorly.
    3) Alpha subunit hydrolyzes GTP to GDP; beta-gamma complex rebinds; GPCR returns to off state.

  • GPCR effectors and second messengers:

    • Phospholipase C

    • Adenylate cyclase

    • Ion channels

  • Common second messengers include IP3, DAG, and cAMP.

  • Activation pathways:

    • IP3/DAG pathway leading to calcium release and PKC activation; IP3 triggers Ca^{2+} release.

    • cAMP pathway leading to PKA activation; regulates multiple targets and gene transcription via transcriptional effects.

  • Deactivation involves G-protein inactivation and degradation/dephosphorylation of signal molecules and target proteins.

  • Example second-messenger molecules:

    • DAG and IP3: activated by GPCRs; include molecules like acetylcholine, epinephrine, CCK, gastrin, oxytocin.

    • cAMP: activated by ADH, dopamine, glucagon, epinephrine, norepinephrine, acetylcholine; degraded by phosphodiesterase (PDE).

  • cAMP signaling kinetics: rapid rise in intracellular cAMP within seconds; PKA activation; can affect rapid enzymatic activity and slower gene transcription.

  • Calcium signaling: involvement in smooth muscle contraction and other Ca^{2+}-dependent processes.

  • One messenger can produce multiple responses, depending on receptor subtype and G-protein coupling (Gs, Gi, etc.).

  • Epinephrine example: different receptors (α1, α2, β1) produce different second messengers and physiological responses via distinct G-proteins (Gs, Gi) and downstream effectors.

Receptors That Signal via Tyrosine Kinases

  • Receptor tyrosine kinases (RTKs) include:

    • Epidermal growth factor (EGF) receptor

    • Insulin receptor

    • Insulin-like growth factor (IGF1) receptor

    • Vascular endothelial growth factor (VEGF) receptor

  • Function: receptors function as enzymes themselves (tyrosine kinase activity) upon ligand binding.

Intracellular (Lipid-Soluble) Receptors

  • Mediate signals via lipid-soluble messengers that cross the membrane and bind to intracellular receptors.

  • Receptors located in cytosol or nucleus and interact with hormone response elements (HRE) on DNA to regulate gene transcription.

  • Examples: Steroid hormones, Vitamin D, Thyroid hormones.

Part 3: Molecular Bases of Physiological Regulation — Part 3

Learning Objectives (Part 3)

  • List the components of the plasma membrane.

  • Explain plasma membrane selective permeability.

  • Explain passive and active transport with examples.

  • Describe resting membrane potential formation.

  • Describe endocytosis and exocytosis mechanisms.

  • Define Starling forces and explain filtration/reabsorption across capillaries.

Plasma Membrane: Components & Functions

  • Components:

    • Lipids (phospholipids, glycolipids)

    • Proteins (integral, peripheral)

    • Carbohydrates

    • Water

    • Divalent cations

    • Cholesterol

  • Functions:

    • Compartmentation

    • Selective transport (resting membrane potential)

    • Information processing (cell signaling)

Membrane Permeability and Transport

  • Smaller, less hydrophilic molecules diffuse more rapidly across the membrane.

  • The interior of the lipid bilayer is hydrophobic, restricting passage of polar molecules; this helps maintain intracellular solute concentrations different from extracellular fluids and compartments.

  • Principle of electroneutrality: equal positive and negative charges across the membrane; free ions are considered in transport dynamics (calcium and magnesium reflect free ion concentrations).

Passive vs Active Transport

  • Passive transport: down a concentration gradient; energy-independent; can be mediated by channels or carriers (facilitated diffusion).

  • Active transport: requires energy; moves solutes against their concentration gradients; always mediated by carriers.

Carriers vs Channels

  • Carriers (carriers) undergo conformational changes that alternately expose solute-binding sites on each side of the membrane to transfer solutes.

  • Channels form pores for specific solutes (ions, water, ammonia); interactions with solutes can be weak.

Ion Channels and Selectivity

  • Ion channels have selectivity filters in which ions are dehydrated; carbonyl oxygen atoms sense dehydrated solutes; Na^+ is smaller than K^+ and may be rejected by a K^+ channel’s selectivity filter.

Ion Channel Types & Examples

  • Na^+ channels (e.g., nicotinic receptor)

  • Mechanosensitive channels (neurons, skeletal muscle)

  • K^+ channels (inner ear, etc.)

Aquaporins

  • Specific water channels expressed by cells that secrete/absorb large amounts of water (e.g., exocrine ducts, kidney).

Active Transport: Energy and Classifications

  • Active transport uses energy or gradients created by other transporters.

  • Classifications by direction and energy use:

    • Uniporters (one solute, one direction)

    • Symporters (co-transport, same direction)

    • Antiporters (exchange, opposite directions)

    • Primary active transport (uses ATP directly)

    • Secondary active transport (driven by gradients created by primary transporters)

    • Tertiary active transport (driven by gradients created indirectly by other transport systems)

Na^+/K^+-ATPase (Sodium-Potassium Pump)

  • Classic example of primary active transport: uses ATP to maintain ion gradients.

  • Transport cycle details (description from the text):

    • During each cycle, 3 Na^+ are pumped out and 2 K^+ are pumped in.

    • 1 ATP molecule is hydrolyzed to phosphorylate the pump, changing its conformation and altering ion affinities.

    • Dephosphorylation returns the pump to its original state.

  • This pump is electrogenic and contributes to the resting membrane potential.

Transcellular Transport of Glucose

  • Transcellular glucose transport involves:

    • Na^+/glucose cotransporter (SGLT) – secondary active transport (symport) that uses the Na^+ gradient.

    • Glucose transporter (GLUT) – passive transporter (facilitated diffusion).

  • This pathway is a classic example of how secondary active transport uses a primary transporter gradient to drive uptake.

Endo- and Exocytosis: Traffic Across the Membrane

  • Endocytosis and exocytosis are membrane trafficking processes for material movement without integral transporters.

  • Endocytosis types:

    • Phagocytosis: ingestion of large particles

    • Pinocytosis: ingestion of small particles or fluids

    • Receptor-mediated endocytosis: involves specific membrane receptors

  • Exocytosis: secretion or membrane addition processes; two pathways:

    • Constitutive secretory pathway: used by all cells; no signal required; exports membrane proteins, extracellular matrix proteins, signaling proteins.

    • Regulated secretory pathway: used by specialized cells; signal is required for vesicle/membrane fusion; neurotransmitter and hormone release.

  • In reality, endocytosis and exocytosis occur simultaneously in cells (e.g., neurons).

Blood/Interstitium Exchange and Starling Forces

  • Exchange between plasma and interstitium occurs via:

    • Vesicular transport (endocytosis/exocytosis): exchangeable proteins

    • Diffusion: O2 and CO2 exchange, diffusion of glucose and amino acids down their gradients

    • Bulk flow: filtration and reabsorption driven by hydrostatic and oncotic pressures

  • Starling principle (Starling forces) explains capillary exchange by integrating hydrostatic and oncotic pressures.

  • Starling equation (Net filtration pressure):
    \text{Net filtration pressure} = (Pc + \pii) - (\pic + Pi)
    where:

  • P_c = capillary hydrostatic pressure

  • P_i = interstitial hydrostatic pressure

  • \pi_c = capillary oncotic pressure (plasma proteins)

  • \pi_i = interstitial oncotic pressure

  • A positive NFP favors filtration; a negative NFP favors reabsorption.

Starling Forces in Capillaries

  • Filtration predominates at the arteriolar end; reabsorption at the venous end.

  • Changes that increase filtration or decrease reabsorption can cause edema.

  • Example values (from the text):

    • Arteriolar end: Pc = 35\ \text{mmHg},\quad \pic = 28\ \text{mmHg}

    • Venous end: Pc = 15\ \text{mmHg},\quad \pic = 28\ \text{mmHg}

    • Interstitial hydrostatic pressure: P_i = 0\ \text{mmHg} at both ends

    • Interstitial oncotic pressure: \pi_i \approx 5\ \text{mmHg} at both ends

Resting Membrane Potential & Electrochemical Gradients

Resting Membrane Potential (RMP)

  • The resting membrane potential of many cells is approximately:
    V_m \approx -70\text{ to }-90\ \text{mV}

  • The RMP arises from a combination of active transport (electrogenic) and passive diffusion.

  • Key players:

    • Na^+/K^+-ATPase (pumps Na^+ out and K^+ in; electrogenic)

    • K^+ leak channels (provide a resting conductance)

    • Negatively charged intracellular proteins and anions (e.g., phosphates, organic anions)

  • The Na^+/K^+ ATPase activity helps maintain the ion gradients that underpin the resting potential.

Electrochemical Gradient & Physiological Relevance

  • The electrochemical gradient combines both the concentration gradient of an ion and the membrane potential.

  • This gradient influences the rate and direction of ion movement and is crucial for processes such as action potentials, muscle contraction, and secondary transport.

Summary of Key Points and Connections

  • Homeostasis is a energy-dependent, integrated process across multiple organ systems, with feedback mechanisms (negative and positive).

  • Proteins are central to physiology, enabling catalysis, transport, signaling, structure, and regulation; their function is modulated by active sites, allosteric changes, and post-translational modifications.

  • Cells communicate via four primary signaling modalities (contact-dependent, paracrine, synaptic, endocrine) and through a variety of receptor types (cell-surface vs intracellular).

  • GPCR signaling is a dominant, versatile mechanism, using second messengers like cAMP, IP3, and DAG to elicit rapid and transcription-level responses; many drugs target GPCRs.

  • Receptor tyrosine kinases and intracellular receptors extend signaling versatility, influencing growth, metabolism, and gene expression.

  • The plasma membrane is a dynamic barrier that controls permeability through channels and carriers; active transport (Na^+/K^+-ATPase) maintains essential ion gradients and resting potentials.

  • Endocytosis and exocytosis regulate membrane turnover and secretion; constitutive vs regulated pathways reflect different cellular needs.

  • The Starling forces provide a quantitative framework for understanding fluid exchange between capillaries and interstitial space; edema can arise from shifts in filtration vs reabsorption.

  • Resting membrane potential emerges from electrogenic pumps and selective permeability, serving as a foundation for excitability and transport processes in physiology.

References to Textbook Concepts (context recap)

  • Four signaling modalities and GPCR mechanisms drawn from Klein et al. and Sjaastad et al. texts.

  • Receptor classes and intracellular signaling pathways summarized from the same sources.

  • Plasma membrane structure, transport, endocytosis/exocytosis, and Starling forces adapted from the Klein Cunningham’s Textbook of Veterinary Physiology and related cell biology resources.

Note: All mathematical expressions use LaTeX formatting as requested. For example, the Starling filtration formula and resting membrane potential values are presented with appropriate symbols and units in … blocks.