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UCSD BIMM 118 - Lecture 4

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Drug Targets Four major drug targets BIMM118 Exceptions Colchicin acts on tubulin Cyclosporin acts via immunophillins etc BIMM118 Drug Targets BIMM118 Drug Targets Drug Targets Receptors Responses to the extracellular environment involve cell membrane or intracellular receptors whose engagement modulates cellular components that generate amplify coordinate and terminate postreceptor signaling via cytoplasmic second messengers Transmembrane signaling is accomplished by only a few mechanisms Transmembrane ion channels open or close upon binding of a ligand or upon membrane depolarization G protein coupled receptors Transmembrane receptor protein that stimulates a GTP binding signal transducer protein G protein which in turn generates an intracellular second messenger Nuclear receptors Lipid soluble ligand that crosses the cell membrane and acts on an intracellular receptor Kinase linked receptors Transmembrane receptor proteins with intrinsic or BIMM118 associated kinase activity which is allosterically regulated by a ligand that binds to the receptor s extracellular domain BIMM118 Drug Targets Receptors Receptors Rapidly acting milliseconds transmembrane ion channels Multi unit complexes with central aqueous channel Upon binding of a ligand channel opening allows a specific ion travel down its concentration gradient Transient cell membrane depolarization post synaptic potential BIMM118 Example Nicotinic acetylcholine receptor Pentameric structure two alpha chains one each beta gamma and delta chain Activation occurs by binding of two molecules ACh to the alpha subunits triggering the opening of the channel for Na and K ions Myasthenia gravis Autoimmune disease caused by inactivating antibodies against NAchR Receptors Many other types of transmembrane ion channels Ion channels are common drug targets Voltage gated channels Gating controlled by membrane polarization depolarization Selectivity Na K or Ca ions Intracellular ligand gated channels BIMM118 Ca controlled K channel ATP sensitive K channel IP3 operated Ca channel in the ER membrane Calcium as Second Messenger Ca very important in regulating cellular and physiological responses Extracellular concentrations are 2 mM EM blood and levels in cytoplasmic vesicles and the ER can reach up to 10mM Baseline cytosolic Ca2 concentration is around 100 nM in resting cells Conc in mM K Na ClCa ECF 4 5 144 114 2 2 ICF 160 7 7 0 0001 High gradient makes this a very fast and sensitive signaling system only slight changes in membrane permeability will result in dramatic changes in the concentration of Ca2 i Low level of Ca2 i is also necessary to facilitate a phosphate oriented cellular metabolism high calcium and high phosphate concentrations are incompatible Evolutionary challenge Maintain calcium gradient Evolvement of proteins that bind Ca2 with high affinity but reject magnesium Two classes of Ca binding proteins BIMM118 membrane integrated unlimited capacity transporter systems Ca channels calcium pumps non membranous limited capacity not only buffering but processing of signal through conformational changes that enable interaction with target proteins Calmodulin Troponin C Calcium as Second Messenger Sources of Ca Extracellular compartment predominantly in nerve cardiac and smooth muscle cells Three types of plasma membrane localized calcium channels Voltage operated calcium channels Action potental depolarizes plasma membrane which results in the opening of voltage dependent calcium channels channels can be opened by increase in extracellular K BIMM118 Each channel protein has four homologous domains each containing six membrane spanning helices the fourth one functions as the voltage sensor Calcium as Second Messenger Three types Type Properties Location Function Blockers L High activation threshold slow inactivation Plasma membrane of many cells main Ca source for contraction in smooth and cardiac muscle Dihydropyridines verapamil diltiazem N Low activation threshold slow inactivation Main Ca source for transmitter release by nerve terminals Conotoxin snail venom T Low activation threshold fast inactivation Widely distributed important in cardiac pacemaker and Purkinje cells Mibefradil verapamil diltiazem Ligand gated calcium channels Calcium channels opened after ligand binding to the receptor e g glutamate NMDA receptor ATP receptor nicotinic ACh receptors muscarinic ACh receptors signal through G Proteins slower prostaglandin receptors Store operated calcium channels BIMM118 Activated by emptying of intracellular stores exact mechanism unknown Calcium as Second Messenger Intracellular compartment predominantly in muscle cells Calcium stored in mM concentrations in endo sarcoplasmatic reticulum bound to Calsequestrin Previously mitochondria were thought to play an important role as Ca stores but the uptake rate is 10x lower than that of the ER SR not useful Calcium release from the ER SR is regulated by two receptors in the ER SR membrane Ryanodine receptors RyR IP3 Receptors IP3R BIMM118 Named after sensitivity to Ryanodine plant alkaloid irreversible inhibitor Very important in skeletal muscle direct coupling of RyRs with the dihydropyridine receptors of the T tubules dihydropyridine receptors are closely related to the L type Ca channels see Ca effects Activity of RyRs in non muscle cell lacking T tubules regulated by cyclic ADP ribose Caffeine reversible activator of RYRs Inositol 1 4 5 triphosphate is produced through the activity of receptor activated phospholipases C diffuses through cytoplasm and binds IP3R Calcium as Second Messenger Removal of Ca Ca pumps Activity of these pumps is induced by increases in cytosolic calcium Plasma membrane Na Ca2 exchanger mainly in excitable cells e g cardiac cells three Na ions are exchanged for one Ca ion Digitalis alkaloids Na K ATPase inhibitors intracellular Na raises Na Ca2 exchange less efficient Ca2 intracellular increases stronger contractions Plasma membrane Ca2 ATPase PMCA two Ca ions are transported per ATP molecule hydrolyzed regulated by CaM PKA or PKC SR ER Ca ATPase SERCA 80 of integral membrane protein of SR target of thapsigargin Ca release from intracellular stores BIMM118 Ca buffers Low affinity but high capacity 50 100 Ca ions molecule Calsequestrin very acidic 37 of amino acids are aspartic and glutamic acid Calreticulin Parvalbumin Calcium as Second Messenger Ca Sensors Annexins Family of proteins w common feature that they interact w membranes in a Ca dependent


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UCSD BIMM 118 - Lecture 4

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