Lec 15-16-2nd Mess-Plast

Lec 15-16-2nd Mess-Plast - A1 Excitation by transmitter due...

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Unformatted text preview: A1 Excitation by transmitter due B1 Excitation by transmitter due to Openmg 6‘" i0“ Channel to closing an ion channel Na+® _ Receptor + Closed /Transmitter Open Heceptog Extracellular side ++ +++ Membrane Cytoplasmic side \ Adenylyl cyciase Open Closed FIGURE 12—9 . K+ Excitatory synaptic action can be initiated in one of two ways: {ll by the direct opening of an ion channel by a transmitter lAi, ATP ——>- CAMP or [2] by the closing of an ion channel by a second messenger {Bl l p A. A transmitter such as ACh or glutamate acts directly on the AA channel protein, opening a channel that is permeable to Na' PFO‘ein kinase A and K‘. t . . 2 catal ic ' B. A transmitter such as serotonin btnds to a receptor and subunfig causes a coupling protein {G} to activate adenylyl cyclase. The /.. : __- CAMP in turn activates a protein kinase, which phosphorylates 2 regulatory; ‘ . an unidentified substrate protein [perhaps the channel itself or SUbumtS a regulatory protein that acts on the channell, causing the K’ channel to close. cAlVIP system - Extracellular V's; .. S‘de 'pad'ren' receptor . ' Cytoplasmic side ‘ 13-2 The synaptic second-messenger systems iden- so far all follow a common plan.The signal-transduction ys illustrated here follow a common sequence of steps Chemical transmitters arriving at receptor molecules in asma membrane activate a closely related family of trans— proteins that activate primary effector enzymes. These .es produce a second messenger that activates a sec- : effector or acts directly on a target (or regulatory) . ic AMP system. This pathway can be activated by a $7 ‘ gic receptor. The second messenger CAMP is produced enylyl cyclase, which is activated by a G protein, so called ,se it requires guanosine triphosphate (GTP) to function. : ,protein here is termed GS because it stimulates the cy— nSome receptors activate a G protein that inhibits the CAMP—dependent protein kinase Phosphoinositol system Arachidonic acid system (382+ release ‘lZ—Lipoxy— genase genase oxygenase Phosphoinositol system. This pathway, activated by a muscarinic acetylcholine (AChl receptor, uses another kind of G protein (qu to activate the primary effector, the enzyme phos- pholipase C (PLCl. This enzyme yields a paiir of second mess sengers, diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3l. in turn, IPg mobilizes Ca2 " from internal stores. DAG acti- vates protein l<inase C (PKCl. Arachidonic acid system. This pathway is activated by a histamine receptor. An unidentified G protein activates phos— phoiipase A2 (PLAzl, which in turn releases the second mes— senger arachidonic acid. Subsequently, arachidonic acid is me- tabolized in a cascade that involves several enzymes, including 5- and 12-Iipoxygenase and cyclooxygenase. Figure 13-3 A G protein-coupled recep- tor contains seven membrane-spanning domains.The BZsadrenergic receptor shown here is structurally simiiar to other G protein-coupled metabotropic recep— tors, including the Bradrenergic and rnus— carinic ACh receptors and rhodopsén. An important functional feature is that the binding site for the neurotransmitter lies in a clett in the receptorthat is embeds dad in the lipid pilayer accessible from the extracellular surface of the cell. The amino acid residue aspartic acid—H?) (Asp113, in dark blue} participates in binding. The part of the receptor indi— cated in brown is the part with which G protein associates. The two serine residues (yellow) are sites for phosphory— lation, which is invoived in inactivating the receptor. (Adapted from Frielie et at. i989.) Extracellular side Cytoplasmic side HOOC itter binding alters conformation of receptor, ‘ ing binding site for G5 protein in the oilayer leads to association of minor receptor complex with (35 protein, byactivating it for GTPeGDP exchange lacement of GDP by GTP causes the a-subunit sociate from the G5 complex, exposmg a ing site for adenylyl cyclase on the otsubunit ubunit binds to and activates cyclase .produce many molecules of CAMP ydrolvsis of the GTP by the (it-subunit returns the unit to its original conformation, causing it to ociate from the cyclase (which becomes ivel and reassociate Wlth a By complex ‘eactivation of cyclase is repeated until the ociation of transmitter returns the receptor to its: riginal conformation G Transmitter Receptor (35 protein F Ade nyly! cyclase Extracellular side Plasma membrane Cytoplasmic side 171 l Phosphodiesterase CAMP ——h- AMP N-terrninal binding site for regulatory l Inactive subunits ' cAMPabinding sites _ CAMPudependent protein kinase Regulatory Naterminal binding/ subunit site for catalytic subunits Active catalytic subunit 1' +ATP Protein Protein P Cellular tinactivel (active) response U Protein phosphatases Pi Figure 135 The CAMP pathway is typical of neuronal second-messenger pathways. Adenylyl cyclase converts ATP into CAMP Four CAMP molecules bind to the two regulatory subunits of the cAMPvdependent protein kinase, liberating the two catalytic subunits, which are then tree to phosphorylate specific substrate proteins that regulate a cellular response, Two kinds of enzymes regulate this pathway. Phosphodiesterases convert CAMP to AM P (which is inactive), and protein phosv phatases remove phosphate groups from the regulator (sub, strate) proteins releasing inorganic phosphate, P.. Serotonergic interneuron Motor neuron Sensory neuron Increased Fl vm ._—i m s-H'r 30 s 10mV Figure 13-12 A slow synaptic action mediated by serotonin closes the S—type K+ channel in Aplysia sensory neurons. A. A serotonergic interneuron makes modulatory synaptic con- nections on the axon terminals and cell body of a mechanore— ceptor sensory neuron. The sensory neuron makes a fast, exci— tatory glutamatergic connection onto a motor neuron. B. Serotonin binds to a metabotropic receptor (5-HT—Fi) that acts through CAMP and CAMP-dependent protein kinase (PKA) to close the S-type (resting) K+ channels in the sensory neu- FONS. Adenylyl cyclase G protein a 5-HT-R C. Application of serotonin 5—HT causes a slow depolari the sensory neuron and a decrease in resting membra ductance lie, an increase in membrane resistance) du . sure oi the S—type K+ channels. The top trace shows th sory neuron membrane voltage and the bottom trace 5 the current injected into the sensory neuron through a i electrode. The brief hyperpolarizing current pulses pro brietC hyperpolarizing voltage responses. The magnitud voltage response is related to the membrane conducta 1. Ohm’s law (AV: Al}. [90. The decrease in membrane i; tance leads to an increase in the size of the voltage pul A 1 Opening of a K4r channel _ by direct action of G-proteln v /Transmitter / Receptor Closed B1 Opening of a K+channei by protein phosphorylation Closed Extracelluiar side + Membrane ‘Cytoplasmic Side \ Adenyiyl B2 cyclase Protein kinase AA FIGURE 12—12 2 t 1 . Synaptic excitation mediated by second messengers need not sufufiiglc involve protein phosphorylation (B) but Channel opening can be / mediated by the direct action of a Geprotein {A} or a second? messenger molecule such as CAMP or CGMP. 2 regulatory % ' subunns Shock Sensory neuron —'\ _ Intemeurons . Gill FIGURE 65—1 Habituation of the gill withdrawal reflex in the marine snail Aplysm is the result of reduced effectiveness of the synapse be- tween sensory neurons and their central target cells in the neu- ral circuit for the reflex. A. This dorsal View of an Aplysia illustrates the respiratory or- gan. the gill, and the mantle shelf, which ends in a fleshy spout called the Siphon. B. This simplified circuit shows key elements involved in the gill-Withdrawal rerlcx as well as sites involved in habituation. in this circuit, about 24 mechanoreccptor sensory neurons located in the abdominal ganglion innervate the siphon skin, only one of which is illustrated here for simplicity. These sensory cells ter- minate on a cluster of six motor neurons that innervate the gill and on several groups of excitatory and inhibitory interneurons [only one of which is illustrated here) that synapse on the motor neurons. Repeated stimulation of the siphon leads to a depression of synaptic transmission between the sensory and motor neurons as well as betWeen certain intemeurons and the motor cells A 1. Control 2. Habituaied :[5 mV Motor neuron W Sensory r/ L," neuron _l \ _ __ _l l \—-'“*—"-‘ l 10 mV 50 msec B 1 week retention l 100!!— _______________________________ __ eel % / V 60 40 Mean percorii oi deleclable conneclions 1 day 1 week Sweets retention retention retention Control Habitualeo FIGURE 65—-2 Longvtcrrri habituation of the gill-withdrawal reflex in Aplvsra is reflected physroloizically in a dramatic depression of synaptic effectiveness between the sensory and motor neurons. iAdapted w” i t from Castellucci, Carew, and Kandel, 19m. A. Cumparison or a synaptic connection between a sensory neuron and :1 motor neuron in a control luntraincdl animal and in an animal that had been subiected to long-term habituation. The synaptic potential in the rumor neuron is still undetectable "1 ~41» l“lb!!‘_l;‘.""'_l .inini' weal-t after t::‘.' B. The mean percentage of detectable connections in habituated animals .it several points in time after iontstenn habituation training. Tail {US} inpu! Sensory neurons Mantle shell Sensory Facilitating neurons interneurons CS ' (control) Siphon skin Sensory neurons A Control Sensitized Motor ________/-_..__._ _mf\ ] 2 mv neuron Sensory v/ neuron — k B Behavior C Synaptic potentials 200 E * 15 ._ > . M 3 150 E E m 2; :3 10 E i ' c 100 E E ‘U a l ._ no 2 50 l 0.5 .2 S 1: E Q 2 E Sensitized Sensitizod Control neurons A Gm sensmzation Sensory X > neuron \’ (V/ Sensnfizing / stxmulus ‘ 63* / /_ Sensory Famhtanng // Ta“ neuron_ mtemeuron —\ . \ i/ 1 \ \ \\, ,1, “\._ _ ‘ \\\ 1 \ \ 76S protein PPP Adam/WI \I‘. CAMP A cydase . x PKC v < CAM P-dependen! Facw Man ng Interneuron Avai‘able Iransmitter Nitype Caz‘ ' channe‘ Releasab‘e transmitter o Sensory "'- : neuron Momr GIutamate neuron receptors 1* 3.000 2.500 2.000 1.500 1.000 500 Number of synaptic boutons per sensory neuron Control Habituated Sensitized B 1. Control 2. Long-term habituation 3. Long-term sensitization Sensory Motor euron neuron Figure 36—0 Long—term habituation and sensitization terminals in control animals with those in long-tern involve structural changes in the presynaptic terminals habituated and sensitized animals. The number is h: of sensory neurons. (Adapted from Bailey and Chen. est in the sensitized animals. 1983.) B. Long-term habituation leads to a loss of synapses A. This histogram compares the numlier or presynapiic long-term sensitization to an increase. Sensory neurons Mantle shelf Sensory Facilitating neurons internourons Tail (US) input CS ' (conlrol) Siphon skin Sensory neurons 3 5 Min W Manllo (CS‘) JELL; Siphon (03") RJJJE Tail (US) M Paired (CS‘) Molor neuron I 5 mV Sensory neuron Pre Post I 20 mV Unpaired (CS') Molor neuron A A Sensory neuron Pra Post 20 "W A CS” Pathway (no preceding activity) B 08+ Pathway (preceding aciivily} Presynaptic membrane US Pathway aecepmf Facilitating protein inlemeuron Adenylyl cyclase Adenylyl cyclase Calmodulin binding site {i Ca2+ channel Calmodulm Caimodulin A gay? 0 O o “A A ATP—WA‘A 00° ATP—iv“ AAA Ca2+ channel 0 A A A (closed) CAMP o Ca2+ A A A A A CAMP i-‘igrm’ 36—8 A molecular model of the synaptic action B. [n the paired pathway (CSW the sensory neuron is underiying classical conditioning. The model is based on active prior to the CS and tints its Cult channels are open the hypothesis that activity in the sensory neurons inedi- when the US is presented. The intracellular Ca3+ binds to ating the conditioned stimulus prior to the presentation calmodulin and in turn interacts with adenyiyl cyclase. of the unconditional stimulus permits an infiux of Ca“ As a result, the adenylyj cyclnge undergoes a confgrma- that enhances the activity of calcium-dependent adenyl- tional change that enhances its ability to synthesize yl cyclase. CAMP in response to serotonin released in the US path- A. m the unpaired pathway “35-) the sensory neuron is way. The greater amount ochMP activates more CAMP~ not active Prior to presentation of the CS, so its Can dependent protein kinase and leads to a substantially channels are closed when the unconditioned stimulus STEM“ amoum 0‘ """511111‘9’ release “"1” WW“ occur (US) is presented. (5-HT, serotonin.) Within” Paired “div”?- Nuclear Signaling GOG: : ' Ubiquitin m hydrolasa Purslsienl kinnaa 6mm“ Cytoplasmic Signaling K+channal Ca2+channel fizfl Molor'neuron ...
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This note was uploaded on 02/12/2010 for the course BME 402 taught by Professor Mel during the Spring '06 term at USC.

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Lec 15-16-2nd Mess-Plast - A1 Excitation by transmitter due...

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