Human Physiology: Membrane Dynamics, Electrical Signaling, and Neurotransmission

Physiology: Foundations and Themes

Definition and Scope

Physiology is the study of the normal functioning of living organisms and their component parts, including chemical and physical processes. It integrates across multiple levels of organization and is closely tied to anatomy.

• Structure-Function Relationship: Structure correlates with function at all levels.

• Energy Requirement: Living organisms require energy for processes.

• Information Flow: Coordinates body functions.

• Homeostasis: Maintains internal stability.

Homeostasis vs. Equilibrium

Homeostasis refers to the maintenance of a stable internal environment, particularly the extracellular fluid (ECF). At homeostasis, the intracellular fluid (ICF) and ECF are in chemical disequilibrium, not equilibrium.

• Osmotic Equilibrium: Water moves freely between ICF and ECF.

• Chemical Disequilibrium: Different ion concentrations in ICF and ECF.

• Electrical Disequilibrium: The inside of the cell is negative relative to ECF.

Control Systems

Control systems regulate variables within acceptable ranges.

• Local Control: Cells near the change initiate the response.

• Reflex Control: Distant cells control the response via a pathway: stimulus → sensor → input signal → integrating center → output signal → target → response.

Feedback Loops

• Negative Feedback: Response counteracts the stimulus, shutting off the response loop (homeostatic).

• Positive Feedback: Response reinforces the stimulus, moving the variable farther from the setpoint.

Membrane Dynamics

Fluid Compartments and Water Content

Water is distributed among body compartments and is essential for physiological function.

• Water Content: About 60% of body weight in a standard 70-kg man (42 liters).

• Variation: Women have less water per kg due to more adipose tissue; infants have more water; water content decreases after age 60.

Table: Water Content by Age and Sex

Age	Male (%)	Female (%)
Infant	65	65
1-9	62	62
10-16	59	57
17-39	61	51
40-59	55	47
60+	52	46

Example: A 58-kg reference woman has total body water equivalent to 50% of her body weight (29 kg). ECF: 19.3 kg; ICF: 9.7 kg; Plasma volume: 4.825 kg.

Osmosis and Osmolarity

Osmosis is the movement of water across a membrane in response to solute concentration gradients.

• Osmotic Pressure: The pressure required to oppose osmosis.

• Molarity: Number of moles of solute per liter (mol/L).

• Osmolarity: Number of osmotically active particles per liter (osmol/L or OsM).

• Normal Human Osmolarity: 280-296 mOsM (rounded to 300 mOsM for calculations).

Examples:

• 1 mole of glucose = 1 osmole (does not dissociate).

• 1 mole of NaCl ≈ 1.8 osmole (dissociates into Na+ and Cl-).

Formula:

$\text{Osmolarity} = \frac{\text{Number of osmoles}}{\text{Liter of solution}}$

Comparing Osmolarities and Tonicity

• Isosmotic: Same number of solute particles per volume.

• Hyperosmotic: More particles per volume.

• Hyposmotic: Fewer particles per volume.

• Tonicity: Describes how a solution affects cell volume (hypotonic, isotonic, hypertonic).

Table: Relationship Between Osmolarity and Tonicity

Tonicity	Hyposmotic	Isosmotic	Hyperosmotic
Hypotonic	Yes	Yes	Yes
Isotonic	No	Yes	Yes
Hypertonic	No	No	Yes

Nature of Solutes:

• Penetrating Solutes: Can cross the cell membrane (e.g., urea).

• Nonpenetrating Solutes: Cannot cross (e.g., NaCl, functionally nonpenetrating).

• Glucose penetrates, then is phosphorylated and becomes nonpenetrating.

Clinical Importance: Understanding osmolarity and tonicity is crucial for making decisions about intravenous (IV) solutions.

Transport Processes Across Membranes

Bulk Flow and Diffusion

Substances move across membranes by several mechanisms:

• Bulk Flow: Mass movement in response to pressure gradients (e.g., blood flow, air flow).

• Diffusion: Movement of molecules from high to low concentration.

• Protein-Mediated Transport: Facilitated diffusion, active transport.

• Vesicular Transport: Endocytosis, exocytosis.

Example: Sodium-potassium pump (Na+-K+-ATPase) maintains chemical and electrical disequilibrium.

Resting Membrane Potential

Principles of Electricity in Physiology

• Law of Conservation of Electrical Charge: Net charge produced is zero.

• Opposite Charges Attract.

• Energy Required: To separate positive and negative charges.

• Conductors vs. Insulators: Cell membrane is a good insulator.

Nernst Equation

Calculates equilibrium potential for an ion:

$E_{\text{ion}} = \frac{61}{z} \log \left( \frac{[\text{ion}]_{\text{out}}}{[\text{ion}]_{\text{in}}} \right)$

• z: Charge of the ion.

• [ion]out: Ion concentration outside the cell.

• [ion]in: Ion concentration inside the cell.

Goldman Equation

Considers concentration gradients and permeability of all penetrating ions.

Resting Membrane Potential: Steady state, not changing; potential energy due to charge difference across membrane. Most cells are closer to EK (-90 mV) than ENa (+60 mV).

Ion Concentrations and Equilibrium Potentials

Ion	Extracellular Fluid (mM)	Intracellular Fluid (mM)	E-Ion at 37°C (mV)
K+	5	150	-90
Na+	145	15	+60
Cl-	108	10	-63
Ca2+	1	0.0001	See concept check Q7

Changes to Membrane Potential

• Caused by changes in permeability to Na+, Ca2+, Cl-, K+.

• Poisons like ouabain (inhibits Na+-K+-ATPase) and tetrodotoxin (blocks Na+ channels) affect membrane potential.

Neurons and Electrical Signaling

Nervous System Organization

• Central Nervous System (CNS): Brain and spinal cord.

• Peripheral Nervous System (PNS): Sensory (afferent) and efferent neurons (somatic motor, autonomic: sympathetic and parasympathetic).

Excitable Tissues

• Neurons and muscle cells establish resting membrane potentials and respond to stimuli by propagating electrical signals.

Ion Channels and Electrical Signals

• Gated Channels: Mechanically, chemically, and voltage-gated.

• Conductance: Ease of ion flow.

• Activation: Opening of channel.

• Inactivation: Closing of channel.

• Channelopathies: Diseases caused by channel mutations (e.g., cystic fibrosis, LQTS).

Ohm's Law

Current flow obeys Ohm's Law:

$I = \frac{V}{R}$

• Resistance: Cell membrane (Rm), cytoplasm (Ri), extracellular fluid (Ro).

• Length Constant: Based on Rm, Ri, Ro.

Voltage Changes: Graded and Action Potentials

• Graded Potentials: Variable strength, short-distance communication; depolarizing (excitatory) or hyperpolarizing (inhibitory).

• Action Potentials: Uniform strength, all-or-none, long-distance signaling.

Action Potentials

Mechanism

• Na+ channels open sequentially, reinforcing depolarization.

• Voltage-gated Na+ (rapid) and K+ (slower) channels open.

• Na+ flows in, K+ flows out.

• Na+-K+-ATPase restores resting potential.

Phases

• Rising Phase: Depolarization to threshold (-55 mV), Na+ influx, overshoot above 0 mV, peak at +30 mV.

• Falling Phase: K+ efflux, hyperpolarization (undershoot), return to resting potential.

Refractory Periods

• Absolute: No action potential can fire (1-2 msec).

• Relative: Action potential can fire with larger stimulus (4 msec).

Conduction

• Depolarization spreads, positive charge flows to adjacent sections.

• Larger neurons and myelinated axons conduct faster (saltatory conduction).

• Cell membrane acts as a capacitor; time constant $\tau = R_m \times C_m$.

Synapses and Neurotransmission

Types of Synapses

• Electrical Synapses: Pass current directly via gap junctions; rapid, bidirectional, synchronized activity.

• Chemical Synapses: Neurocrine molecules (neurotransmitters, neuromodulators, neurohormones) carry information across synaptic cleft.

Receptors

• Ligand-Gated Ion Channels (ICR): Rapid, ionotropic responses.

• G Protein-Coupled Receptors (GPCR): Slower, metabotropic responses via second messengers.

Major Neurocrines

• Acetylcholine (ACh): Synthesized from choline and acetyl CoA; cholinergic neurons; nicotinic (ion channel) and muscarinic (GPCR) receptors.

• Amines: Serotonin (tryptophan), histamine (histidine), dopamine, norepinephrine, epinephrine (tyrosine).

• Amino Acids: Glutamate (excitatory), aspartate (excitatory), GABA (inhibitory).

• Peptides: Substance P (pain), opioid peptides (enkephalins, endorphins), CCK, vasopressin, ANP.

• Lipids: Eicosanoids, endogenous ligands for cannabinoid receptors.

• Purines and Gases: Additional info: ATP, nitric oxide act as signaling molecules.

Neurotransmitter Synthesis and Release

• Peptides synthesized in cell body, processed via transcription, translation, post-translational modification.

• Neurotransmitters stored in synaptic vesicles, released by exocytosis.

• Neurotoxins (tetanus, botulinum) inhibit exocytosis.

Termination and Recycling

• Neurotransmitter activity terminated by reuptake, enzymatic degradation, or diffusion.

• Acetylcholine is broken down by acetylcholinesterase and recycled.

Intensity of Stimuli

• Stronger stimuli produce higher frequency of action potentials and more neurotransmitter release.

• Patterns in CNS are variable and complex.

Example: Myasthenia gravis is an autoimmune disease destroying ACh receptors in skeletal muscle.

Additional info: Channelopathies, such as cystic fibrosis and LQTS, illustrate the importance of ion channels in health and disease.