Week 5 Year 1 Med

What are the two structural classes of membrane proteins?

Integral (transmembrane) proteins: embedded within the lipid bilayer, often span it via alpha-helical segments; transport substances, act as receptors, participate in signalling. Peripheral proteins: loosely attached to inner or outer membrane surface; support cytoskeletal attachment, signalling and membrane organisation.

What are the five functional classes of membrane proteins?

Adhesion proteins (attach cells to other cells/ECM), Communication proteins (gap junctions — direct cell-cell exchange), Recognition proteins (identify self vs non-self via glycoproteins), Receptor proteins (bind ligands → signal transduction), Transport proteins (regulate movement of substances across membrane).

What are gap junctions and what is their role?

Communication proteins that allow molecules up to 500 daltons to pass directly between neighbouring cells. Coordinate cellular activity and synchronise function in tissues such as cardiac muscle.

What are recognition proteins?

Glycoproteins with carbohydrate chains projecting outside the cell; allow cells to identify other cells and distinguish self from non-self. Crucial for immune responses, blood group identification and tissue compatibility.

What is the difference between ionotropic and metabotropic receptors?

Ionotropic: ligand binding directly opens an ion channel. Metabotropic: activate intracellular signalling pathways via second messengers. Both convert extracellular signals into intracellular responses (signal transduction).

What are the types of passive transport proteins?

Ion channels (specific ions: Na+, K+, Ca2+, Cl-), Leak channels (always open; e.g. K+ leak channels), Aquaporins (rapid water transport), Uniporters (transport one molecule at a time).

What is the difference between primary and secondary active transport?

Primary active transport: uses ATP directly (e.g. Na+/K+ ATPase — 3 Na+ out, 2 K+ in). Secondary active transport: uses electrochemical gradients created by primary transport; Symporters move molecules in the same direction; Antiporters move in opposite directions.

What molecules can freely cross the plasma membrane?

Small non-polar molecules and lipid-soluble substances (O2, CO2, steroid hormones) and some small uncharged molecules.

What molecules cannot freely cross the plasma membrane?

Ions, large polar molecules, charged molecules and most proteins — these require transport proteins or vesicular transport.

What are the three mechanisms by which molecules cross membranes?

Simple diffusion (small non-polar molecules through lipid bilayer), Facilitated diffusion (protein-mediated, down gradient; glucose transporters, ion channels), Active transport (against gradient, requires ATP; Na+/K+ ATPase).

What are the two types of vesicular transport?

Endocytosis (materials enter the cell: phagocytosis, pinocytosis, receptor-mediated endocytosis) and Exocytosis (materials released from the cell: hormone secretion, neurotransmitter release).

What is the fluid mosaic model?

Describes the plasma membrane as: Fluid (lipids and proteins move laterally within the membrane) and Mosaic (many different molecules arranged in a dynamic patchwork pattern). Components: phospholipids, membrane proteins, cholesterol and carbohydrates.

What is the role of cholesterol in the plasma membrane?

Located between phospholipids; regulates membrane fluidity; stabilises membrane structure; prevents the membrane from becoming too rigid or too fluid.

What is the glycocalyx?

Carbohydrates attached to membrane proteins and lipids forming glycoproteins and glycolipids; project outward from the membrane. Functions: cell recognition, communication, immune system identification and cell adhesion.

What is exocytosis?

The process by which intracellular vesicles fuse with the plasma membrane, releasing their contents into the extracellular fluid. Mechanism: proteins synthesised in ER → Golgi packaging → vesicles move to plasma membrane → dock and fuse → contents released.

What are SNARE proteins and their role in exocytosis?

v-SNARE (synaptobrevin) on the vesicle and t-SNARE (syntaxin and SNAP-25) on the plasma membrane interact to pull the vesicle and membrane together, enabling fusion. Calcium ions often trigger vesicle fusion.

What is the difference between constitutive and regulated exocytosis?

Constitutive: occurs continuously without a signal; used for secretion of ECM proteins, membrane proteins and lipids. Regulated: vesicles accumulate and release only in response to a signal (e.g. neurotransmitter release, insulin secretion from pancreatic B cells).

What are the three types of endocytosis?

Phagocytosis (engulfment of large particles like bacteria; performed by macrophages and neutrophils), Pinocytosis (uptake of small dissolved molecules and extracellular fluid; occurs continuously), Receptor-mediated endocytosis (highly specific; uses clathrin-coated pits; e.g. LDL uptake).

What happens to a vesicle after endocytosis?

Vesicle fuses with early endosome → low pH causes receptor-ligand dissociation → cargo is either recycled back to membrane, moves to late endosome, or fuses with lysosome for degradation.

What is the resting membrane potential (RMP) and what maintains it?

The stable electrical potential difference across the cell membrane when not actively transmitting a signal; typically -70 mV in neurons. Maintained by: Na+/K+ ATPase (3 Na+ out, 2 K+ in), K+ leak channels and unequal ion distribution across the membrane.

Why is RMP closer to the potassium equilibrium potential than the sodium equilibrium potential?

There are ~100x more K+ leak channels than Na+ leak channels, so the membrane is much more permeable to K+; membrane potential is closer to EK (-94 mV) than ENa (+61 mV).

What is threshold in neuronal signalling?

The critical level of membrane depolarisation (~-55 mV) that must be reached to trigger an action potential; caused by sufficient opening of voltage-gated Na+ channels. If not reached, no action potential occurs (all-or-nothing principle).

What is depolarisation?

The reduction in negative membrane potential, making the inside of the cell less negative (more positive). Voltage-gated Na+ channels open → rapid Na+ influx → membrane potential moves from -70 mV toward +30 mV. Positive feedback: more depolarisation → more Na+ channels open.

What is repolarisation?

After the peak of the action potential, voltage-gated K+ channels open (slower than Na+ channels) → K+ efflux out of the cell → membrane potential returns toward negative.

What is hyperpolarisation?

When membrane potential becomes more negative than RMP (drops to ~-80 to -90 mV) because K+ channels remain open longer than needed. Makes the neuron less likely to fire another action potential.

What are the absolute and relative refractory periods?

Absolute refractory period: Na+ channels are inactivated → no new action potential possible regardless of stimulus size. Relative refractory period: membrane is hyperpolarised → a stronger than normal stimulus is required to trigger an action potential. Function: ensures one-way propagation and limits AP frequency.

What is saltatory conduction?

Action potentials "jump" between nodes of Ranvier in myelinated axons rather than propagating continuously. This increases conduction speed and improves signal transmission efficiency.

What are the three parts of a neuron and their functions?

Cell body/soma: contains nucleus and organelles; metabolic centre; integrates signals; produces proteins for neurotransmission. Dendrites: branched projections receiving signals from other neurons; conduct signals toward cell body. Axon: long single projection conducting action potentials away from cell body; terminals release neurotransmitters at synapses.

What is a synapse?

The junction between two neurons (or neuron and effector). Most synapses are chemical and use neurotransmitters. Structure: presynaptic terminal (synaptic vesicles), synaptic cleft (small gap), postsynaptic membrane (receptors).

What are the steps of chemical synaptic transmission?

Action potential arrives → Ca2+ influx through voltage-gated Ca2+ channels → vesicle fusion → neurotransmitter released via exocytosis → diffuses across synaptic cleft → binds postsynaptic receptors (ligand-gated ion channels) → ion channels open → change in membrane potential.

What determines whether a synapse is excitatory or inhibitory?

Both the neurotransmitter released (presynaptic) AND the receptor type on the postsynaptic membrane. Glutamate is usually excitatory; GABA is usually inhibitory. Acetylcholine: nicotinic receptor = excitatory; muscarinic receptor = can be inhibitory.

What is an EPSP vs IPSP?

EPSP (excitatory postsynaptic potential): depolarisation — brings membrane closer to threshold (typically due to Na+ influx). IPSP (inhibitory postsynaptic potential): hyperpolarisation — moves membrane further from threshold (typically due to Cl- influx or K+ efflux).

How is synaptic transmission terminated?

Reuptake of neurotransmitter into the presynaptic neuron, enzymatic degradation in the synaptic cleft, or diffusion away from the synapse.

What is the sliding filament hypothesis of muscle contraction?

Thin actin filaments slide over thick myosin filaments, shortening the sarcomere (functional unit of muscle). The filaments themselves do NOT shorten — they slide past each other.

What is the size principle of motor unit recruitment?

Small motoneurons (produce less force, fatigue-resistant) are recruited first; larger motoneurons (produce more force but fatigue faster) are recruited progressively as demand increases.

What are the three compartments of the leg and their functions?

Anterior compartment: dorsiflexion and toe extension (deep fibular nerve, anterior tibial artery). Lateral compartment: foot eversion (superficial fibular nerve, fibular artery branches). Posterior compartment: plantarflexion and toe flexion (tibial nerve, posterior tibial and fibular arteries).

What muscles form the posterior compartment (superficial layer) and where do they insert?

Gastrocnemius, soleus and plantaris — these combine to form the calcaneal (Achilles) tendon inserting on the calcaneus.

What is Virchow's triad?

The three factors predisposing to deep vein thrombosis: Venous stasis (slow/stagnant blood flow), Endothelial injury (exposes collagen/tissue factor → activates coagulation), Hypercoagulability (increased tendency to clot: cancer, pregnancy, OCP, genetic disorders).

What are the signs and symptoms of DVT?

Unilateral leg swelling, calf pain/tenderness, warmth, redness or skin discolouration, tightness or heaviness. Signs: calf tenderness, increased calf circumference, dilated superficial veins, pitting oedema.

What are the complications of DVT?

Pulmonary embolism (thrombus breaks off → travels to lungs → obstructs pulmonary arteries; symptoms: dyspnoea, chest pain, tachycardia, haemoptysis), Post-thrombotic syndrome (chronic venous insufficiency, leg swelling, skin pigmentation, venous ulcers), Recurrent DVT, Venous gangrene (rare — severe obstruction → tissue ischaemia/necrosis).

How does heparin work as an anticoagulant?

Unfractionated heparin enhances antithrombin III activity → inhibits thrombin (Factor IIa) and Factor Xa → prevents conversion of fibrinogen to fibrin. LMWH (e.g. enoxaparin) more specifically inhibits Factor Xa with more predictable pharmacokinetics.

How does warfarin work as an anticoagulant?

Vitamin K antagonist — inhibits vitamin K recycling → prevents activation of vitamin K-dependent clotting factors (II, VII, IX and X) produced in the liver.

What are DOACs and how do they work?

Direct Oral Anticoagulants. Direct Factor Xa inhibitors (rivaroxaban, apixaban, edoxaban) block Factor Xa → prevent thrombin generation. Direct thrombin inhibitors (dabigatran) directly inhibit thrombin (Factor IIa) → prevent fibrinogen → fibrin conversion.

What is bioavailability?

The fraction of an administered drug that reaches systemic circulation in an active form. IV drugs = 100% bioavailability. Oral drugs often have reduced bioavailability due to incomplete absorption and first-pass metabolism in the liver.

What are the two phases of drug metabolism in the liver?

Phase I: oxidation, reduction and hydrolysis (mainly by CYP450 enzyme system) — chemically modifies the drug. Phase II: conjugation reactions — add polar molecules to increase water solubility for excretion.

What is Michaelis-Menten kinetics in drug metabolism?

Describes enzyme-mediated drug metabolism: at low drug concentrations elimination follows first-order kinetics; at high concentrations enzymes become saturated → elimination approaches zero-order kinetics. Typical of drugs with enzyme-limited metabolism.

What is renal drug excretion and what processes are involved?

The most common route of drug elimination. Involves: glomerular filtration (passive), tubular secretion (active, removes protein-bound drugs) and tubular reabsorption (passive; lipid-soluble drugs reabsorbed).

What is drug half-life?

The time required for the plasma drug concentration to decrease by 50%. Constant in first-order kinetics; not constant in zero-order kinetics.

What is the CYP450 enzyme system?

A group of liver enzymes (major isoforms: CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP1A2) involved in Phase I drug metabolism (oxidation, reduction, hydrolysis). Converts drugs into water-soluble metabolites for excretion.

What is enzyme inhibition of CYP450 and what are its clinical effects?

CYP inhibitors reduce CYP450 activity → slow drug metabolism → increased drug concentration → increased risk of toxicity or adverse effects. Examples: erythromycin, ketoconazole.

What is enzyme induction of CYP450 and what are its clinical effects?

CYP inducers increase CYP450 activity → accelerate drug metabolism → decreased drug concentration → reduced therapeutic effect. Examples: rifampicin, carbamazepine, phenytoin.

How does grapefruit juice interact with drugs?

Grapefruit juice inhibits CYP3A4 in the intestinal wall → increased drug concentrations. Affected drugs include calcium channel blockers, some statins and immunosuppressants.

How does warfarin interact with antibiotics via CYP450?

Warfarin is metabolised mainly by CYP2C9. Some antibiotics (e.g. metronidazole, trimethoprim) inhibit CYP enzymes → increased warfarin levels → increased bleeding risk.

How does vitamin K-rich food interact with warfarin?

Warfarin inhibits vitamin K-dependent clotting factors. Foods high in vitamin K (spinach, kale, broccoli, Brussels sprouts) reduce the anticoagulant effect of warfarin → increased risk of thrombosis if intake increases significantly.

How does alcohol interact with warfarin?

Acute alcohol intake inhibits warfarin metabolism → increased bleeding risk. Chronic alcohol intake induces CYP enzymes → reduced warfarin effectiveness.

What is pre-test probability?

The estimated likelihood that a patient has a disease before performing a diagnostic test. Determined by symptoms, clinical history, risk factors, physical examination and clinical scoring systems (e.g. Wells score for DVT).

What is sensitivity in diagnostic testing?

The ability of a test to correctly identify patients who have the disease (true positive rate). A highly sensitive test produces few false negatives. Principle: SnNout — a Sensitive test with a Negative result rules out disease. Example: D-dimer has high sensitivity for DVT.

What is specificity in diagnostic testing?

The ability of a test to correctly identify patients who do not have the disease (true negative rate). A highly specific test produces few false positives. Principle: SpPin — a Specific test with a Positive result rules in disease. Example: compression ultrasound is more specific for DVT.

Why is D-dimer high sensitivity but low specificity for DVT?

D-dimer (fibrin degradation products) increases with any condition causing clot formation AND breakdown, including infection, inflammation, trauma, pregnancy, cancer and surgery — so many false positives occur.

How does pre-test probability affect use of the D-dimer test?

Low pretest probability: D-dimer appropriate — negative result rules out DVT, avoids unnecessary imaging. Moderate probability: D-dimer useful — negative = unlikely; positive = proceed to ultrasound. High pretest probability: D-dimer NOT appropriate — even a negative may not rule out DVT; proceed directly to imaging.

What is the Wells Score used for?

A clinical scoring system used to estimate pre-test probability of deep vein thrombosis (DVT). Risk factors increasing the score include: recent surgery, immobilisation, active cancer, previous DVT and unilateral leg swelling.

What is the popliteal artery and what does it supply?

Continuation of the femoral artery behind the knee. Divides into: anterior tibial artery (supplies anterior compartment) and posterior tibial artery (supplies posterior compartment). The fibular/peroneal artery (branch of posterior tibial) supplies the lateral compartment.

What nerve supplies each compartment of the leg?

Anterior compartment: deep fibular nerve. Lateral compartment: superficial fibular nerve. Posterior compartment: tibial nerve. All arise from the sciatic nerve, which divides in the popliteal fossa.

What is the common fibular nerve at risk for and why?

It wraps around the neck of the fibula making it vulnerable to injury at this site (e.g. fracture, cast pressure). It divides into the deep fibular nerve (anterior compartment) and superficial fibular nerve (lateral compartment).

What is the role of the Na+/K+ ATPase in generating the resting membrane potential?

Pumps 3 Na+ out and 2 K+ in per cycle (net positive charge removed) → creates electrochemical gradients; contributes to the negative interior of the cell and maintains RMP and osmotic balance.

How do voltage-gated Na+ channels contribute to the action potential?

At threshold they open rapidly → Na+ rushes into cell → rapid depolarisation (upstroke to ~+30 mV). They then quickly inactivate (within ~1 ms) stopping further Na+ entry. Absolute refractory period occurs while channels are inactivated.

What is the difference between continuous and saltatory conduction?

Continuous conduction: unmyelinated axons — AP regenerates at every point along the membrane (slower). Saltatory conduction: myelinated axons — AP jumps between nodes of Ranvier (faster, more energy efficient).

What are the key ion movements at each phase of the action potential?

Resting: K+ leak out, small Na+ leak in, pump maintains balance. Depolarisation: rapid Na+ influx (voltage-gated). Repolarisation: K+ efflux (voltage-gated, delayed). Hyperpolarisation: excess K+ efflux. Return to RMP: K+ channels close, Na+ channels reset, Na+/K+ pump restores gradients.

What two things determine whether a postsynaptic cell fires an action potential?

Summation of EPSPs (excitatory postsynaptic potentials) and IPSPs (inhibitory postsynaptic potentials). If the sum of inputs depolarises the membrane to threshold, an action potential is triggered.