2.1 Homeostasis, Cell Function, Membrane Transport & Resting Potential

Why this area matters

Physiology opens day 1 of the PLE. The general and cellular physiology area (15 of 100 items in the 2025 Table of Specifications) asks you to:

• explain normal homeostasis;
• show how a deranged cellular process produces a sign or symptom;
• choose the test that reveals the derangement.

Most items are short clinical scenarios such as hyperkalemia after a crush injury, digoxin toxicity or glucosuria on an SGLT2 inhibitor. To answer them, you need the mechanism, not just the definition.

Levels of organization and the internal environment

Living systems are organized as cells, then tissues, organs, organ systems and finally the organism. Cells survive because they are bathed in the extracellular fluid (ECF), the "internal environment" that Claude Bernard described. Homeostasis, Walter Cannon's term, is the maintenance of nearly constant conditions in that fluid.

Women and older adults have a lower water fraction, about 50%, because they carry more adipose tissue. Infants have a higher fraction, about 70% to 75%.

Control systems of the body

• Negative feedback opposes the initial change. Examples are the arterial baroreceptor reflex, the regulation of blood CO2 by ventilation, and hormone axes such as cortisol inhibiting ACTH.
• Gain expresses how effective a feedback system is:

$$\text{Gain} = \frac{\text{Correction}}{\text{Error}}$$

Worked example. A transfusion would raise mean arterial pressure from 100 to 175 mmHg if there were no reflexes. With intact baroreceptors, pressure rises only to 125 mmHg. The correction is 125 - 175 = -50 mmHg, and the remaining error is 125 - 100 = +25 mmHg. The gain is therefore -50/25 = -2. Temperature control, by comparison, has a gain of about -33.

• Positive feedback amplifies the change. It is useful when it drives a process to completion: oxytocin and cervical stretch in labor (the Ferguson reflex), the mid-cycle LH surge, the clotting cascade, and opening of sodium channels during an action potential. It is harmful as a "vicious cycle", for example when severe hemorrhage lowers coronary perfusion, weakens the heart and lowers pressure further.
• Feed-forward (adaptive) control anticipates an error. The cerebellum, for instance, adjusts rapid movements before sensory feedback arrives.

Functional systems of the cell

Genetic control of protein synthesis and cell reproduction

DNA is transcribed in the nucleus by RNA polymerase II into pre-mRNA. After capping, splicing and polyadenylation, the mature mRNA is translated on ribosomes. Gene expression is controlled at the promoter by transcription factors, many of them hormone receptors: steroid and thyroid hormones act this way, which explains their slow onset.

The cell cycle runs G1, then S (DNA synthesis), then G2, then M (mitosis). Cyclins and cyclin-dependent kinases drive it forward. p53 halts cells with damaged DNA at the G1/S checkpoint, and the retinoblastoma (Rb) protein holds cells in G1 until it is phosphorylated. Cells are classified by how they use the cycle:

• labile cells (epithelia, marrow) divide continuously;
• stable cells (hepatocytes, renal tubular cells) sit in G0 but can re-enter the cycle;
• permanent cells (neurons, cardiac and most skeletal muscle) cannot divide.

Cellular Homeostasis & Resting Membrane Potential

The semipermeable plasma membrane maintains stark electrochemical disequilibrium between the intracellular fluid (ICF) and extracellular fluid (ECF). This distribution is sustained by active transport and selective passive ion permeability.

Intracellular vs. Extracellular Ion Concentrations

Biophysical Equations of Membrane Potential

The equilibrium potential for any single permeant ion species is calculated using the Nernst Equation:

$E_{ion} = \frac{RT}{zF} \ln\left(\frac{[ion]_{out}}{[ion]_{in}}\right) = \frac{61.5}{z} \log_{10}\left(\frac{[ion]_{out}}{[ion]_{in}}\right) \text{ mV at } 37^\circ\text{C}$

Where $R$ is the universal gas constant, $T$ is absolute temperature ($310\text{ K}$), $z$ is the valence of the ion ($+1$ for $Na^+$ and $K^+$, $+2$ for $Ca^{2+}$, $-1$ for $Cl^-$), and $F$ is Faraday's constant.

Because the plasma membrane is simultaneously permeable to multiple ionic species, the steady-state Resting Membrane Potential ($V_m$) is governed by the Goldman-Hodgkin-Katz (GHK) Voltage Equation:

$V_m = \frac{RT}{F} \ln \left( \frac{P_K [K^+]_o + P_{Na} [Na^+]_o + P_{Cl} [Cl^-]_i}{P_K [K^+]_i + P_{Na} [Na^+]_i + P_{Cl} [Cl^-]_o} \right)$

At rest, the relative permeabilities of a typical mammalian neuronal membrane are:

$P_K : P_{Na} : P_{Cl} \approx 1.0 : 0.04 : 0.45$

Because $P_K$ is roughly 25-fold higher than $P_{Na}$ due to constitutively open non-gated potassium leak channels (inward-rectifying $K_{ir}$ and two-pore domain $K_{2P}$ channels such as TASK and TREK), the resting membrane potential ($-70\text{ mV}$ in large neurons, $-90\text{ mV}$ in skeletal muscle fibers) sits close to the equilibrium potential of potassium ($-90\text{ mV}$). Small changes in extracellular potassium (hypokalemia or hyperkalemia) cause immediate, clinically significant shifts in excitable cell membrane polarization and cardiac rhythmicity.

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Primary & Secondary Active Transport

Transmembrane transport mechanisms fall into passive processes (simple diffusion, facilitated diffusion via GLUT uniporters) and active processes requiring cellular energy expenditure.

Primary Active Transport

Primary active transport couples the movement of solutes against their thermodynamic electrochemical gradients directly to the enzymatic hydrolysis of adenosine triphosphate (ATP).

1. $Na^+/K^+$ ATPase Pump:
   • Translocates $3\ Na^+$ ions outward and $2\ K^+$ ions inward per molecule of ATP hydrolyzed.
   • Maintains the high intracellular $[K^+]$ and low intracellular $[Na^+]$ gradients fundamental to all secondary active transport and excitable tissue polarization.
   • Electrogenic nature: Ejects 3 positive charges for every 2 positive charges brought inside, generating a net outward positive current that directly hyperpolarizes the membrane by $-3\text{ to }-5\text{ mV}$.
   • Consumes roughly 30% to 40% of basal metabolic energy in resting humans.
   • Pharmacology: Specifically inhibited by cardiac glycosides (digoxin, digitoxin, ouabain), which bind the extracellular $K^+$-binding site in the phosphorylated $E_2$-P conformation.
2. Calcium ATPases (SERCA & PMCA):
   • SERCA (Sarco/Endoplasmic Reticulum $Ca^{2+}$-ATPase): Pumps $2\ Ca^{2+}$ ions from the cytoplasm into the SR lumen per ATP molecule, lowering cytosolic calcium to resting submicromolar levels ($< 100\text{ nmol/L}$) to permit muscle relaxation.
   • PMCA (Plasma Membrane $Ca^{2+}$-ATPase): Extrudes $Ca^{2+}$ across the sarcolemma into the extracellular environment.
3. $H^+/K^+$ ATPase Pump:
   • Expressed in gastric parietal cells (pumping protons into the gastric lumen against a gradient of roughly 3 million to 1) and renal $\alpha$-intercalated cells (mediating systemic acid excretion).

Secondary Active Transport

Secondary active transport couples the downhill thermodynamic movement of an ion (predominantly $Na^+$, moving down the steep inward electrochemical gradient established by the primary $Na^+/K^+$ pump) to the uphill movement of a co-transported solute against its gradient.

• Symport (Cotransport): Solutes move in the same direction across the membrane.
  • SGLT1 & SGLT2: Sodium-glucose cotransporters. SGLT2 in the renal proximal convoluted tubule ($S_1$ segment) reabsorbs $\sim 90\%$ of filtered glucose ($1\ Na^+ : 1\text{ glucose}$); SGLT1 in the intestinal enterocyte and renal $S_3$ segment reabsorbs glucose and galactose ($2\ Na^+ : 1\text{ monosaccharide}$). SGLT2 inhibitors (empagliflozin, dapagliflozin) induce therapeutic glucosuria.
  • NKCC2 ($Na^+/K^+/2Cl^-$ cotransporter): Expressed on the apical membrane of the thick ascending limb of the loop of Henle. Electroneutral transport of $1\ Na^+$, $1\ K^+$, and $2\ Cl^-$, driving countercurrent multiplication. Inhibited by loop diuretics (furosemide).
  • NCC ($Na^+/Cl^-$ cotransporter): Located in the early distal convoluted tubule. Inhibited by thiazide diuretics.
• Antiport (Countertransport / Exchange): Solutes move in opposite directions.
  • $Na^+/Ca^{2+}$ Exchanger (NCX): Extrudes $1\ Ca^{2+}$ from the cell in exchange for the influx of $3\ Na^+$ ions. Driven by the sodium gradient. When digitalis inhibits the $Na^+/K^+$ ATPase, intracellular $[Na^+]$ rises, dissipating the inward sodium gradient and slowing NCX forward activity. Intracellular $Ca^{2+}$ accumulates, augmenting myocardial contractility (positive inotropy).
  • $Na^+/H^+$ Exchanger (NHE3): Located on the apical brush border of renal proximal tubules, mediating sodium reabsorption and proton secretion necessary for luminal bicarbonate reclamation.