Plasma membrane structure and transport ط Transportation across cell membrane ط passive ط active ط facilitated diffusion with examples for each ط Clinical correlation Cystic fibrosis Loss of membrane transport system D

Introduction · Lipid nature in memb restricts movement of inorganic ions or charged organic molecules · They do not diffuse significantly because of interaction with water and exclusion of charges and lipids · Diffusion of inorganic ions, carbohydrates and AAs is too slow · Specific translocation mechanism for movement of substances across membrane is needed: · Transportation Direction: fig Uniport: 1 molecule to 1 side 2- Antiport: 2 molecules to 2 sides 3- Symport: 2 molecules to 1 side

Plasma membrane transport 1. Diffusion (simple diffusion) 2. Mediated Transport System (facilitated) A. Membrane Channels (facilitated): B. Transporters (facilitated): o Passive transport system (passive diffusion): o Active transport system: C. Ionophores:

1. Diffusion (simple diffusion) Simple diffusion, move down concentration (from high to low) Each step involves equilibrium of solutes between two states fig5.28, 1). Solute Enters 2). Solutes transvers across memb 3). solute leave the memb · Diffusion of gases (O2, N2, CO2, NO) occur rapidly and depends on conc. gradient · Water diffuses readily via gaps created by FA chains (transitory space) · Uncharged lipophilic substances depend on lipid solubility (FA, steroids) · Water soluble substance are stripped of water interaction and regained on leaving (sugars, inorganic ions - slow)

2. Mediated Transport System (facilitated) · Uptake of nutrients and maintain ion conc and control metabolism · Change in aqueous area created in prt structure by AA lining · Differ from simple diffusion: rapid & saturation kinetic fig5.29, · Facilitated transport involves intrinsic protein with amphipathic feature · Classified on the basis of mechanism of translocation and energetic Table5.4

2. Mediated Transport System (facilitated) · Common character: - Specificity: a) inorganic anions & cations (e.g. Na+, K+, Ca++, HPO4++, Cl–, HCO3–) b) uncharged organic compounds (e.g. AAs & sugars) c) Integral prt is specific for substances transported (transporters of permease, pump) - Structural: a) Mitoch transport of ADP & ATP e) RBCs transport of D-glucose is 10x greater than L-glucose - Rate: rate of transport is faster than simple diffusion

2. Mediated Transport System · Common steps: fig Recognition: of specific substrates by transporter in aqueous environment through specific binding site 2- Translocation : of solutes by creating a channel between environment controlled by gradient mech and conformation of prt chain occur 3- Release: of solutes occur when conc in the new compartment is lower than the intial side and because a change in conformation decrease affinity 4- Recovery: of transporter to its original state (conformation) to accept another solute.

2. Mediated Transport System A. Membrane Channels (facilitated): · Moves down concentration gradient (from high to low) · The intrinsic protein creates an aqueous hole and · depend on size and charge of molecule, lead to rapid and specific movement · Do not bind to protein · Do not change transported protein

2. Mediated Transport System A. Membrane Channels (facilitated): · Example: i) Na+-channel: - controlled by voltage-gate channel causing transmembrane potential (open \ shut gate) - depolarization lead to opening and rapid increase of intracellular Na+ (nerve & muscle) - permitting movement of Na+ 10x greater than K+ and Ca++ - present in most plasma memb and mitoch - consist of a single large glycopeptide and several smaller glycoproteins fig5.34 ii) Cl–-channel: - controlled by cAMP modifying Cl– channel (e.g. in cystic fibrosis)

2. Mediated Transport System A. Membrane Channels (facilitated): · Example: iii) Nicotinic Acetylcholine-channel (acetylcholine receptor) fig binding to specific agent (agonist) – nicotine or Ach - this will open the channel (in neuromusclural junction) allowing selected cations in - present in neurons - consists of 5 polypeptides subunits When neurons excited they release Ach into neuromuscular junction & dissufse to skeletal muscle memb where 2 Ach interact with nAch receptor (αsubunit) and opens the channel allowing selective cations to move in. This will cause transmemb potential leading to series of event producing muscle contraction - inhibited by neurotoxins & toxins (snake) - succinylcholine (muscle relaxant) activates the channel

2. Mediated Transport System B. Transporters (facilitated): · physically bind to molecules and ions to moves across the membrane · Specific for transported solutes · Can be inhibited (competitively or non-competitively) · Passive or active Table5.5

2. Mediated Transport System B. Transporters (facilitated): o Passive transport system (passive diffusion): - Do not change transported molecules - Do not require energy for transportation - Moves molecules down conc gradient - different from simple diffusion by * demonstrates saturation kinetics * structural specificity of molecules movement * specific inhibition of solutes

2. Mediated Transport System B. Transporters (facilitated): o Passive transport system (passive diffusion): - Example: i) glucose transporters, uniport ii) Anion Transporters (Cl–/HCO3–), antiport fig5.38 * a passive exchange by down conc gradient with antiport mech iii) Mitoch transport system fig5.39: example: ADP-ATP, Pi-OH–, Malate-Pi, Aspartate-Glutamate Uncoupling proteins (traslocates H+) generate heat (in brown adipose tissue)

2. Mediated Transport System B. Transporters (facilitated): o Active transport system: - can change transported molecules - require energy for transportation (hydrolysis of ATP or use of electrogradient of Na+ or H+) - can move molecules against conc gradient - same as passive diffusion: * demonstrates saturation kinetics * structural specificity of molecules movement * specific inhibition of solutes - different from passive diffusion: * require utilization of energy * occur by conformation changes

2. Mediated Transport System B. Transporters (facilitated): o Active transport system: - Example: i) Primary active transport: chemical, utilize ATP directly - Na+/K+ pump (ATPase), antiport fig5.41 P transporter: phosphoryrylation#deposph V transporter: lysosomes, endosomes, golgi F transporter: mitoch, chloroplasts - Ca++ pump, uniport Transport Ca++ as 2ndry messenger to hormones, regulating cell process Trnasient opening of channel, causing release from store (End Retic, sacroplasmic Retic)

2. Mediated Transport System B. Transporters (facilitated): o Active transport system: - Example: ii) Secondary active transport: electrochemical gradient, use another source of energy as gradient of Na+ ions - Na+-dependent transport of glucose and AAs moves sugars, AAs & Ca++ by aymport mech

2. Mediated Transport System B. Transporters (facilitated): o Group transport system fig Chemical modify transported molecules -example: * sugar uptake by bact involves phosphorylation * uptake of AAs by some mammalian cells (glutamyl cycle)

2. Mediated Transport System C. Ionophores: · Small molecules from bacterial origin, antibiotic · Facilitates movement of molecules and inorganic ions across the lipid bilayer membrane by binding 1. Mobile Carriers: diffuse back and forth carrying ions 2. Ionophores Channels: ions diffusing via

Clinical Correlations: 1. Cystic Fibrosis (Cl– channel) cc5.3 Multi-organ disease Most common in Caucasians Characterized by reduced Cl– permeability leading to luminal dehydration Most common cause is deletion of a single phenylalanine cFTR gene (regulatetor) Main manifestation is pulmonary obstruction (cause by thickening of mucosa) Diagnosed by increase in Cl– in sweat Pancreatic dysfunction (exocrine) lead to steatorrhea Still under study with surgical removal best solution

Clinical Correlations: 2. Diseases of loss of membrane transport system cc5.4 Diabetes, loss of glc absorption by intestine Fru malabsorption syndromes Hartnup’s disease, decrease in neutral AA transportation in intestine and renal tubules Cystinuria, abnormal cystine and basic AA (lys & arg) lead to cystine stone Hypophosphatemia (vit D resistance & rickets), abnormal renal absorption of Pi Muscle, liver & brain pathology (little known)