Cell Membrane Physiology

Membrane Transport

Membrane transport refers to the regulated movement of water, solutes, macromolecules, and particles across the lipid bilayer and associated membrane systems. In mammalian cells, the plasma membrane is approximately 7–10 nm thick and consists of an amphipathic phospholipid bilayer with cholesterol, glycolipids, and embedded proteins. Its hydrophobic core imposes a major energetic barrier to charged and polar molecules, making transport highly selective and central to cellular excitability, epithelial secretion, nutrient uptake, renal tubular handling, drug disposition, and maintenance of intracellular ionic composition.

Physicochemical determinants of membrane permeability

Passive permeability through the lipid phase is governed by size, charge, polarity, lipid solubility, and concentration gradient. Small non-polar molecules such as O₂, CO₂, N₂, and steroid hormones cross readily by simple diffusion. Water crosses slowly through the lipid bilayer but rapidly through aquaporins. Ions such as Na⁺, K⁺, Ca²⁺, Cl⁻, and HCO₃⁻ have negligible lipid permeability because hydration shells and charge separation make entry into the hydrophobic core energetically unfavourable.

For non-electrolytes, net flux is approximated by Fick’s law:

J = P × A × (C_out − C_in), where J is flux, P permeability coefficient, A membrane area, and the concentration difference is the driving force. For charged solutes, electrochemical rather than purely chemical gradients determine movement. Thus, although Na⁺ is more concentrated extracellularly, its movement also depends on membrane potential and permeability pathways.

Classification of membrane transport

Mechanism	Energy requirement	Direction relative to gradient	Key properties	Clinical relevance
Simple diffusion	None	Down chemical gradient	Non-saturable; proportional to gradient and lipid solubility	Gas exchange; diffusion of volatile anaesthetics and steroid hormones
Facilitated diffusion	None	Down electrochemical gradient	Saturable; competitive; protein-mediated	GLUT-mediated glucose transport; urea transport in renal medulla
Primary active transport	Direct ATP hydrolysis or equivalent	Against electrochemical gradient	Saturable; inhibited by metabolic poisons	Na+/K+-ATPase, Ca2+-ATPase, H+/K+-ATPase
Secondary active transport	Indirect; uses ion gradient	One solute down, another against gradient	Co-transport or counter-transport	SGLT2 in proximal tubule; Na+/Ca2+ exchanger in myocardium
Vesicular transport	ATP- and GTP-dependent cytoskeletal processes	Not gradient-dependent	Bulk movement of macromolecules or particles	Endocytosis of LDL; neurotransmitter exocytosis; antigen presentation

Passive transport and osmotic water movement

Passive transport does not require metabolic energy and proceeds towards thermodynamic equilibrium. In simple diffusion, flux is not saturable because no binding site is involved. By contrast, facilitated diffusion displays Michaelis–Menten-type kinetics, with a maximum transport rate (V_max) and an affinity constant analogous to K_m. This distinction is important in physiology: insulin-sensitive GLUT4 translocation increases skeletal muscle and adipose glucose uptake by increasing transporter density, whereas GLUT2 in liver and pancreatic β-cells has high capacity and lower affinity, allowing glucose sensing across physiological post-prandial ranges.

Water transport is determined by osmotic gradients. Normal plasma osmolality is approximately 275–295 mOsm/kg. Effective osmolality, or tonicity, depends on solutes that do not freely cross the membrane; Na⁺ and its accompanying anions dominate extracellular tonicity, whereas urea contributes to measured osmolality but is relatively ineffective across many cell membranes. Rapid correction of chronic hyponatraemia risks osmotic demyelination; standard guidance limits correction to about ≤8–10 mmol/L in 24 hours, and lower targets are used in high-risk patients.

Active transport and maintenance of cellular gradients

Active transport is essential because passive fluxes would otherwise dissipate ionic asymmetry. The Na⁺/K⁺-ATPase extrudes 3 Na⁺ in exchange for 2 K⁺ per ATP hydrolysed, making it electrogenic and a major determinant of intracellular Na⁺, cell volume, and secondary active transport. Typical extracellular and intracellular concentrations are approximately: Na⁺ 140 mmol/L extracellular versus 10–15 mmol/L intracellular; K⁺ 3.5–5.0 mmol/L extracellular versus 120–150 mmol/L intracellular; free cytosolic Ca²⁺ around 100 nmol/L versus extracellular ionised Ca²⁺ around 1.1–1.3 mmol/L. These steep gradients underpin excitability, secretion, contraction, and signalling.

Primary active transporters include P-type ATPases such as Na⁺/K⁺-ATPase, sarco/endoplasmic reticulum Ca²⁺-ATPase, plasma membrane Ca²⁺-ATPase, and gastric H⁺/K⁺-ATPase. Clinically, the H⁺/K⁺-ATPase is inhibited irreversibly by proton-pump inhibitors; omeprazole is commonly dosed at 20–40 mg once daily, with maximal acid suppression requiring active pump turnover rather than simply plasma half-life. Cardiac glycosides inhibit Na⁺/K⁺-ATPase, raising intracellular Na⁺, reducing Na⁺/Ca²⁺ exchange, and increasing intracellular Ca²⁺; digoxin has a narrow therapeutic range, commonly cited as approximately 0.5–2.0 micrograms/L, with toxicity promoted by hypokalaemia.

Secondary active and vesicular transport

Secondary active transport uses stored energy in ion gradients. Symport moves solutes in the same direction, as with Na⁺-glucose co-transport in intestine and proximal renal tubule. Antiport moves solutes in opposite directions, as with Na⁺/H⁺ exchange and Na⁺/Ca²⁺ exchange. This distinction is heavily tested because inhibition of one process alters gradients driving another: SGLT2 inhibition reduces proximal glucose reabsorption and causes glycosuria, osmotic diuresis, and modest natriuresis.

Vesicular transport handles substrates too large or complex for carrier-mediated movement. Endocytosis may be phagocytic, pinocytic, receptor-mediated, or caveolae-dependent. Receptor-mediated endocytosis is saturable and specific, exemplified by LDL receptor internalisation via clathrin-coated pits; inherited LDL receptor defects impair hepatic LDL clearance and cause familial hypercholesterolaemia. Exocytosis requires vesicle docking, priming, and calcium-dependent fusion, particularly in endocrine and neuronal secretion. Thus, membrane transport integrates biophysics, metabolism, and signalling, and provides multiple pharmacological targets relevant to clinical medicine and MRCP-level physiology.

Transport Proteins

Transport proteins are integral membrane proteins that mediate selective movement of solutes across the lipid bilayer by binding the substrate and undergoing conformational change. Unlike ion channels, they do not usually form a continuously open aqueous pore; transport is therefore saturable, stereo-selective and competitively inhibitable. Typical turnover is approximately 10²–10⁴ molecules/s, far slower than ion channels, which may conduct 10⁶–10⁸ ions/s.

Functional classification

Class	Energy source	Directionality	Key examples	Clinical relevance
Facilitated diffusion	Electrochemical gradient	Downhill only	GLUT1, GLUT2, GLUT4; urea transporters	GLUT4 insulin-dependent uptake in skeletal muscle/adipose tissue; GLUT1 deficiency causes infantile seizures, developmental delay and low CSF glucose
Primary active transport	ATP hydrolysis or light/redox energy	Uphill possible	Na+/K+-ATPase, H+/K+-ATPase, Ca2+-ATPases, ABC transporters	Targets of digoxin, proton-pump inhibitors; ABC efflux contributes to multidrug resistance
Secondary active transport	Ion gradient, usually Na+ or H+	Uphill transport of one solute coupled to downhill movement of another	SGLT1/2, Na+/Ca2+ exchanger, Na+/H+ exchanger, NKCC2	SGLT2 inhibitors in diabetes, heart failure and CKD; loop diuretics inhibit NKCC2

Carrier mechanism and kinetics

Most carriers operate by the alternating access model: substrate binds to a high-affinity site exposed to one side of the membrane, the protein undergoes an occluded intermediate conformation, then opens to the opposite side where altered affinity permits release. This explains saturability and competition. Transport rate follows Michaelis–Menten-like kinetics:

v = V_max[S] / (K_m + [S]), where V_max reflects transporter number and turnover, and K_m is the substrate concentration at half-maximal transport, inversely related to apparent affinity.

Exam-relevant examples include GLUT transporters. GLUT1 has a low K_m of approximately 1–2 mmol/L, ensuring basal glucose uptake in erythrocytes and the blood–brain barrier. GLUT2 has a higher K_m of approximately 15–20 mmol/L, functioning as a hepatic and pancreatic beta-cell glucose sensor. GLUT4 is insulin-responsive and translocates from intracellular vesicles to the plasma membrane via PI3K–Akt signalling; impaired translocation is central to insulin resistance.

Primary active transporters

The Na⁺/K⁺-ATPase is a P-type ATPase that exports 3 Na⁺ and imports 2 K⁺ per ATP hydrolysed, generating an electrogenic outward positive current. It maintains intracellular Na⁺ around 10–15 mmol/L and K⁺ around 120–150 mmol/L, compared with extracellular Na⁺ approximately 135–145 mmol/L and K⁺ approximately 3.5–5.0 mmol/L. Its alpha subunit is inhibited by cardiac glycosides. Digoxin reduces Na⁺ extrusion, diminishing Na⁺/Ca²⁺ exchanger activity and increasing intracellular Ca²⁺. Therapeutic serum digoxin is commonly targeted at 0.5–0.9 ng/mL in heart failure; toxicity risk rises particularly above 2.0 ng/mL, and is potentiated by hypokalaemia, renal impairment and interacting drugs such as amiodarone and verapamil.

The gastric H⁺/K⁺-ATPase exchanges luminal K⁺ for intracellular H⁺ in parietal cells. Proton-pump inhibitors are prodrugs activated in the acidic canaliculus and irreversibly inhibit the pump; examples include omeprazole 20–40 mg once daily and pantoprazole 40 mg once daily, with pharmacodynamic acid suppression lasting 24–48 hours despite short plasma half-lives of approximately 1–2 hours.

Ca²⁺-ATPases maintain steep calcium gradients: cytosolic free Ca²⁺ is approximately 100 nmol/L, extracellular Ca²⁺ about 1.1–1.3 mmol/L ionised, and sarcoplasmic reticulum Ca²⁺ substantially higher. SERCA pumps resequester Ca²⁺ during muscle relaxation; PMCA extrudes Ca²⁺ across the plasma membrane.

Secondary active transporters

Secondary active transport exploits gradients generated mainly by Na⁺/K⁺-ATPase. Transport may be symport, where solutes move in the same direction, or antiport, where they move oppositely. SGLT1, in small intestine and late proximal tubule, has high affinity and transports 2 Na⁺:1 glucose; SGLT2, in the early proximal tubule, has lower affinity but high capacity and reabsorbs roughly 90% of filtered glucose. The normal renal threshold for glycosuria is approximately 10 mmol/L plasma glucose, though variable.

SGLT2 inhibitors, such as dapagliflozin 10 mg once daily and empagliflozin 10 mg once daily, induce glycosuria and natriuresis. Their benefit extends beyond glycaemia: major trials including EMPA-REG OUTCOME, DAPA-HF, EMPEROR-Reduced and DAPA-CKD demonstrated reductions in heart failure hospitalisation and renal disease progression. Current cardiology, diabetes and nephrology guidance supports their use in heart failure with reduced or preserved ejection fraction and in chronic kidney disease down to trial- and product-specific eGFR thresholds, commonly around 20–25 mL/min/1.73 m² for cardiorenal indications.

ABC and SLC transporter families

Human transporters are dominated by two major superfamilies. SLC transporters are mostly facilitated or secondary active carriers, including GLUTs, SGLTs, organic anion transporters and organic cation transporters. These govern drug absorption, renal tubular secretion and blood–brain barrier penetration. ABC transporters use ATP binding and hydrolysis; examples include P-glycoprotein, encoded by ABCB1, which exports digoxin, ciclosporin, tacrolimus, direct oral anticoagulants and many cytotoxics. Overexpression causes multidrug resistance in malignancy and limits CNS drug entry. ABCC7, better known as CFTR, is structurally an ABC protein but functions as a regulated chloride and bicarbonate conductance, explaining cystic fibrosis when defective.

Ion Channels

Ion channels are transmembrane protein pores permitting rapid, energetically passive movement of ions down their electrochemical gradients. Flux rates are typically 10⁶–10⁸ ions/second, several orders of magnitude faster than carrier-mediated transport. They determine membrane excitability, secretion, contraction, epithelial transport and intracellular signalling. For MRCP Part 1, the key distinction is that channels alter permeability, not the ion gradient itself; the latter is maintained by pumps and exchangers.

Core biophysical principles

Ion movement through an open channel is governed by the electrochemical driving force: current is proportional to conductance × (membrane potential − equilibrium potential). The equilibrium potential for a single ion is predicted by the Nernst equation; physiologically important approximate values are E_K −90 mV, E_Na +60 mV, E_Cl −65 to −75 mV and E_Ca +120 mV. Thus opening Na⁺ or Ca²⁺ channels depolarises cells, whereas opening K⁺ channels hyperpolarises or repolarises them. Cl⁻ channel effects depend on the chloride equilibrium potential and developmental/tissue context.

Selectivity arises from pore geometry and electrostatic interactions within the selectivity filter. K⁺ channels discriminate K⁺ over Na⁺ despite Na⁺ being smaller, because dehydrated K⁺ is stabilised optimally by carbonyl oxygens in the filter. Ca²⁺ channels achieve high selectivity via negatively charged residues that preferentially coordinate divalent cations. Many channels exhibit multiple states: closed, open and inactivated/desensitised. Inactivation is critical for action potential refractoriness and for drug effects.

Classification by gating mechanism

Class	Trigger	Examples	High-yield clinical/pharmacological relevance
Voltage-gated	Change in membrane potential sensed by charged transmembrane domains	Nav, Cav, Kv	Action potentials; antiarrhythmics, antiepileptics, local anaesthetics
Ligand-gated ionotropic receptors	Extracellular neurotransmitter binding	Nicotinic ACh receptor, GABAA, NMDA, AMPA	Neuromuscular transmission, anaesthesia, epilepsy, excitotoxicity
Intracellular ligand-gated	Cytosolic second messengers or nucleotides	IP3 receptor, ryanodine receptor, cAMP/cGMP-gated channels, KATP	Calcium release, malignant hyperthermia, insulin secretion
Mechanosensitive	Membrane stretch or mechanical deformation	Piezo channels, stretch-activated channels	Baroreception, touch, endothelial responses
Leak channels	Constitutive probabilistic opening	K+ leak channels, background Na+ conductance	Dominant determinant of resting membrane potential

Voltage-gated channels

Voltage-gated Na⁺ channels open rapidly when threshold is reached, typically around −55 mV in neurons, producing the action potential upstroke. They then inactivate within 1–2 ms, explaining the absolute refractory period. Local anaesthetics and class I antiarrhythmics bind preferentially to open or inactivated Na⁺ channels, producing use-dependent block; rapidly firing tissue is therefore more susceptible. Clinically relevant examples include lidocaine for ventricular arrhythmias, flecainide in selected supraventricular arrhythmias, and phenytoin/carbamazepine/lamotrigine for seizure disorders through stabilisation of the inactivated Na⁺ channel state.

Voltage-gated Ca²⁺ channels include L-type channels in myocardium, vascular smooth muscle and endocrine cells, and N/P/Q-type channels at presynaptic terminals. L-type blockade by dihydropyridines causes vasodilatation; verapamil and diltiazem additionally depress AV nodal conduction. Ca²⁺ entry through L-type channels triggers calcium-induced calcium release via ryanodine receptors in cardiac myocytes. In skeletal muscle, the dihydropyridine receptor functions primarily as a voltage sensor mechanically coupled to the ryanodine receptor.

Voltage-gated K⁺ channels mediate repolarisation and after-hyperpolarisation. Delayed rectifier currents are central to cardiac action potential phase 3. Blockade of the rapid delayed rectifier current I_Kr, encoded by KCNH2/hERG, prolongs the QT interval and predisposes to torsades de pointes; this is a common mechanism of drug withdrawal or warning, including with some macrolides, fluoroquinolones, antipsychotics and antiarrhythmics.

Ligand-gated and intracellular channels

The nicotinic acetylcholine receptor is a pentameric cation channel permeable to Na⁺ and K⁺, producing end-plate depolarisation. Competitive blockade by non-depolarising neuromuscular blockers is antagonised by increasing acetylcholine with acetylcholinesterase inhibitors; depolarising blockade with suxamethonium reflects persistent receptor activation followed by inactivation/desensitisation. GABA_A receptors are ligand-gated Cl⁻ channels; benzodiazepines increase channel opening frequency, while barbiturates increase duration, explaining synergistic CNS depression.

NMDA receptors require glutamate binding, co-agonist glycine or D-serine, and depolarisation to remove Mg²⁺ block. Their high Ca²⁺ permeability links synaptic activity to plasticity but also to excitotoxicity. AMPA receptors mediate fast excitatory transmission predominantly via Na⁺ influx.

Intracellular Ca²⁺ release channels include IP₃ receptors on endoplasmic reticulum and ryanodine receptors on sarcoplasmic reticulum. Mutations in RYR1 predispose to malignant hyperthermia, typically triggered by volatile anaesthetics or suxamethonium; definitive treatment is dantrolene 2.5 mg/kg IV, repeated as required, with high-dose supportive care. K_ATP channels couple metabolism to excitability: in pancreatic β-cells, rising ATP closes K_ATP channels, depolarising the membrane and opening voltage-gated Ca²⁺ channels to trigger insulin secretion. Sulfonylureas close these channels; diazoxide opens them.

Channelopathies: examination relevance

• Cystic fibrosis: CFTR is an ATP-gated epithelial Cl⁻ channel; defective chloride and bicarbonate secretion causes dehydrated secretions. Ivacaftor potentiates gating mutations such as G551D.
• Long QT syndromes: loss-of-function K⁺ channel mutations or gain-of-function late Na⁺ current prolong repolarisation; QTc is generally abnormal at >450 ms in men and >470 ms in women, with high torsades risk when >500 ms.
• Hypokalaemic periodic paralysis: Ca_v1.1 or Na_v1.4 channel mutations cause episodic weakness precipitated by carbohydrate load, rest after exercise or hypokalaemia.
• Myasthenic syndromes: congenital defects of nicotinic receptor channels or presynaptic Ca²⁺ channels impair neuromuscular transmission; Lambert–Eaton syndrome targets presynaptic P/Q-type Ca²⁺ channels.

Membrane Potentials

Membrane potential is the voltage difference across the lipid bilayer, conventionally expressed as intracellular potential relative to extracellular fluid. It arises because biological membranes are selectively permeable, ionic concentration gradients are maintained by active transport, and impermeant intracellular anions create a Gibbs-Donnan influence. For most mammalian cells, the resting membrane potential is negative, typically −60 to −90 mV in neurones and skeletal muscle, approximately −85 to −95 mV in ventricular myocytes, and more variable in smooth muscle, often −40 to −70 mV.

Equilibrium potentials and the Nernst equation

The equilibrium potential for an ion is the membrane voltage at which its electrical and chemical driving forces are exactly balanced. At 37°C, the Nernst equation is commonly written:

E_ion = 61.5/z × log₁₀([ion]_out/[ion]_in) mV, where z is ionic valence.

Ion	Approximate extracellular concentration	Approximate intracellular concentration	Typical equilibrium potential	Physiological implication
K+	3.5–5.0 mmol/L	120–150 mmol/L	−90 mV	Dominant determinant of resting membrane potential due to high resting K+ permeability
Na+	135–145 mmol/L	10–15 mmol/L	+60 mV	Rapid inward current during action potential upstroke in neurones, skeletal muscle and myocardium
Cl−	95–105 mmol/L	5–30 mmol/L	Approximately −60 to −80 mV	Stabilises membrane potential; inhibitory postsynaptic currents in many neurones
Ca2+	Ionised 1.1–1.3 mmol/L	Free cytosolic approximately 100 nmol/L	+120 mV	Large inward electrochemical gradient; signalling and excitation-contraction coupling

Resting membrane potential: Goldman-Hodgkin-Katz principles

Real membranes are permeable to several ions simultaneously, so resting potential is better described by the Goldman-Hodgkin-Katz voltage equation, weighted by relative permeability. At rest, P_K greatly exceeds P_Na, mainly through leak and inward rectifier K⁺ channels, so the membrane potential lies close to E_K but is less negative because of a small Na⁺ leak and other conductances. The Na⁺/K⁺-ATPase maintains gradients by extruding 3 Na⁺ in exchange for 2 K⁺ per ATP hydrolysed; it is electrogenic, contributing a few millivolts of hyperpolarisation, but its major role is long-term preservation of transmembrane gradients.

Extracellular potassium is particularly important. Hyperkalaemia reduces the K⁺ gradient, making E_K less negative and initially depolarising cells; sustained depolarisation inactivates voltage-gated Na⁺ channels, reducing excitability and conduction. Hypokalaemia hyperpolarises the membrane and may prolong repolarisation in cardiac tissue. These principles explain ECG changes in potassium disorders and the cellular basis of arrhythmogenesis.

Graded potentials and action potentials

Graded potentials are local, decremental voltage changes whose amplitude is proportional to stimulus intensity. They summate spatially and temporally and are typical of postsynaptic potentials, receptor potentials and some smooth muscle responses. Action potentials are regenerative, all-or-none events initiated when depolarisation reaches threshold, commonly around −55 mV in neurones, although threshold varies with channel density, recent activity and extracellular ion composition.

Neuronal and skeletal muscle action potential

1. Resting state: voltage-gated Na⁺ channels are closed but activatable; K⁺ conductance predominates.
2. Depolarisation: rapid opening of voltage-gated Na⁺ channels causes inward Na⁺ current and membrane potential approaches E_Na, typically peaking near +30 to +40 mV.
3. Repolarisation: Na⁺ channels inactivate within milliseconds while delayed rectifier K⁺ channels open, producing outward K⁺ current.
4. After-hyperpolarisation: persistent K⁺ conductance drives potential transiently closer to E_K, contributing to relative refractoriness.

The absolute refractory period reflects Na⁺ channel inactivation and prevents immediate re-excitation; the relative refractory period occurs during after-hyperpolarisation, when a larger stimulus is required. Myelination increases conduction velocity by reducing capacitance and increasing membrane resistance, enabling saltatory conduction between nodes of Ranvier. Typical conduction velocities range from 0.5–2 m/s in unmyelinated C fibres to 50–120 m/s in large myelinated Aα fibres.

Cardiac membrane potentials

Cardiac action potentials are longer than neuronal action potentials because repolarisation is delayed by Ca²⁺ influx and channel kinetics. Ventricular myocytes have a stable resting potential near −90 mV. Phase 0 is fast Na⁺ entry; phase 1 is transient outward K⁺ current; phase 2 is the plateau due to L-type Ca²⁺ influx balanced by K⁺ efflux; phase 3 is repolarisation via delayed rectifier K⁺ currents; phase 4 is resting potential. In sinoatrial nodal cells, phase 4 spontaneous depolarisation is generated by the funny current I_f, T-type Ca²⁺ current and declining K⁺ conductance; phase 0 depends predominantly on L-type Ca²⁺ channels rather than fast Na⁺ channels.

Drug class/example	Membrane potential target	Exam-relevant effect
Class I antiarrhythmics; local anaesthetics such as lidocaine	Voltage-gated Na+ channels	Reduce phase 0 upstroke and conduction velocity; use-dependent block is greater in rapidly firing tissue
Class III antiarrhythmics, e.g. amiodarone, sotalol	K+ channels	Prolong repolarisation, action potential duration and refractory period; may prolong QT
Non-dihydropyridine calcium-channel blockers	L-type Ca2+ channels	Slow SA and AV nodal depolarisation and conduction
Digoxin	Na+/K+-ATPase inhibition	Raises intracellular Na+, reduces Na+/Ca2+ exchange and increases intracellular Ca2+; narrows safety margin for afterdepolarisations

For MRCP purposes, membrane potentials integrate electrochemical gradients, selective permeability and channel gating. The key conceptual hierarchy is: concentration gradients set equilibrium potentials; permeability determines the actual membrane potential; voltage-gated conductances generate excitability; and altered extracellular ions or channel-modifying drugs predictably disturb conduction, refractoriness and arrhythmia risk.