Receptors and Ion Channels
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1 Receptors and Ion Channels Laurie Kellaway Senior Lecturer Department of Human Biology Tel
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3 What are the two types of Neurotransmitter receptors Ionotropic receptors these have an ion channel incorporated into their structure Binding of the ligand opens the associated ion channels Share similarities with voltage-gated and gap-junction ion channels All three types have multiple membrane spanning regions Eg.s nictotinic Ach receptor, GABAa receptor & glycine receptors Glut. Ionotropic have similar structure but belong to diffferent family GABA & NMDA receptors can bind a number of different ligands & the main ligand for the receptor
4 Metabotropic receptors more complex, are relatively slower (have longer lasting effects), but denote more flexibility i.t.o. cell function (a) an enzyme is activated directly such as some peptide receptors eg NGF, Insulin (b) activation of second messenger cascade typically the receptor is linked to a G-Protein, that stimulates activity of intracellular enzymes that may directly affect channel function or even gene transcription rates
5 Autoreceptors These are receptors located on the presynaptic terminal Ligand for this class of receptor is the NT released by the neuron on which they are located: hence autoreceptor Role:homeostatic function: regulate NT release In catecholaminergic & serotoninergic neruons regulate synthesis of NT Somatodendritc autoreceptors regulate firing rate of neuron Autoreceptors are invariably metabotropic! Negative feed-back mechanism limits NT release by reducing Ca ++ influx
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8 1 sub-unit of nachr Orientation of membrane spanning subunit; Amino & carboxy termini in e.c. space Membrane spanning segments TM1 TM4 Side view of 5 subunits Tm2 subunit orientated towards pore
9 Top view of above, noting relative positions of TM1 to TM 4 TM2 in each sub-unit form majoriity of structure of pore
10 Ionotropic Glu. Reptors Original model analagous to nachr: 2 loops e.c & 2 loops i c.between TMs Ionotropic Glu. Reptors Current model: TM2 is kinked within memebrane thus loop between TM2 & TM3 and COOH loop become cyoplasmic
11 Diagram of NMDA receptor
12 General model of metabotropic receptor NH2 terminus e.c.-binds Glutamate transmembrane domains TM1 to TM7 3 loops aas both ec & ic TM3 TM5 TM6 Area for NTx association with G proteins Binding of NTx causes conformational change & exposes i3 (aas indicated in red on i3 loop) for binging G Pr i3
13 How do the modulatory NTxs cause postsynaptic changes? Metabotropic receptors are modulatory ultimate result is turning off or on ionic currents Ach, Glutamate and GABA ( besides ionotropic effect) also bind metabotropic receptors - producing long lasting postsynaptic effects Biogenic amines are also metabotropic; Purines (ATP, ADP, UTP & adenosine) active at purinogenic receptors also in this class All act through a second messenger cascade: bound receptor activates a transducer, which in turn affects an EFFECTOR, this lead to production of second messenger. A second effector can then be activated this scheme can stop at any point depending on receptor and cell type
14 What is a G Protein? main tranducers in 2 nd messenger cascade consists of α,β,γ subunit binds guanine nucleotides α subunit is bound to GDP when ligand binds it promotes exchange of GDP for GTP α a bound GTP causes dissociation from other two subunits - once this happened the primary effector is activated In turn the separated α subunit has intrinsic GTPase activity that converts bound GTP to GDP hence reassociation of subunits turns off cascade
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16 RECEPTOR EFFECTOR
17 Acetycholine Muscarinic G P Norepinephrine Β receptor G s NT Receptor G-Protein + PLC DAG PIP 2 ADENYLATE CYCLASE ATP camp Effector 2 nd Messenger IP3 Ca++ PKC PKA Mediator CaM Kinase + Other targets
18 What is the adenylate cyclase 2 nd mesenger system? G s stimulate adenylate cyclase system this increases production of cyclic adenosine monophosphate (camp) in cell. camp can produce a number of intracellular effects some channels are directly gated There are also camp dependent protein kinases There are also camp response elements on DNA that can affect transcription rates Regulation: adenylate cyclase synthesizes camp, while phosphodiestrase metabolizes - activation of receptor can lead to changes in phosphodiesterase activity ( often via changes in Ca++ levels) Cyclic nuceotides important in transduction of signals also include cyclic guanosine monophosphate (cgmp)
19 Turned OFF state Hydrolyzing conversion to GDP Turned ON state GTPase activity of G protein serves as timer & amplifier NT activates receptor initiates the GTPase timing by displacement of GDP by GTP
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21 Role of camp and Ca ++ in the activation pathways of transcription camp is the best characterized intracellular signaling pathway Major feature regulation of large number of genes
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23 Cross talk between kinases and phophatases
24 Interaction of signal transduction pathways in the brain
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26 Endoplasmic reticulum Ca ++ channels
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