Download Free Medical Neurotransmitter and Receptors PowerPoint Presentation

Neurotransmitter and Receptors PowerPoint Presentation

DOWNLOAD MEDICAL POWERPOINT PRESENTATION

About This Presentation

Description : Check out this medical presentation on Neurology, which is titled "Neurotransmitter and Receptors", to know about Neurotransmitter and Receptors.

Tags : Neurology, Neurotransmitter, Receptors

Published on : Aug 23, 2021 | Views : 2165 | Downloads : 4

Shareable Url :

Embed Code :

Comment

Transcript

Slide 1-

Neurotransmitter and Receptors Synaptic transmission: The release of neurotransmitter by a presynaptic cell and the detection and response of the neurotransmitter by the postsynaptic cell Objective of these lectures: to learn the specific mechanisms of the principal neurotransmitters, to introduce basic neuropharmacology. Touch on physiological role now, explore in later lectures in more depth. Classification of neurotransmission Fast neurotransmission Neurotransmitter directly activates ligand-gated ion channel receptor Neuromodulation Neurotransmitter binds to G-protein coupled receptor to activate a chemical signaling cascade
Slide 2-

Outline Survey of neurotransmitter structures Fast neurotransmission: glutamate, GABA, glycine, acetylcholine Metabolism and vesicular transport Reuptake and degradation Receptor systems Pharmacology: agonists and antagonists Synaptic integration Neuromodulation: catecholamines, serotonin, histamine, neuropeptides Overview of G-protein signaling Metabolism and vesicular transport Reuptake and degradation Receptor systems, coupling, downstream targets Pharmacology: agonists and antagonists Unconventional neurotransmitters endocannabinoids, NO
Slide 3-

Survey of the major neurotransmitters
Slide 4-

A word about classifying neurotransmitters Some neurotransmitters have fast and neuromodulatory modes of function, some exclusively one type or the other Fast mode: ion channel receptors (ionotropic receptors) Modulatory mode: G-protein coupled receptors (metabotropic receptors)
Slide 5-

H o w a r e G A B A r e c e p t o r s r e g u l a t e d ? Fast neurotransmission, simplified Metabolism and vesicular transport Reuptake and degradation Receptor systems Pharmacology: agonists and antagonists for study and therapy
Slide 6-

Glutamate fast neurotransmission Synthesis, packaging, reuptake, degradation (error - should be EAAT)
Slide 7-

Molecular diversity of glutamate receptors: 3 types, based on sensitivity to pharmacological agents: AMPA, kainate, N-methyl d-aspartate (NMDA) AMPA: homotetramers or heterotetramers assembled from Glu R1-4 subunits NMDA: heterotetramers that contain an NR1 subunit, and a subunit from the NR2 family Kainate: heterotetramers containing subunits from the KA1,2 family, and from the GluR5-7 family
Slide 8-

AMPA receptor structure (NMDA, kainate receptors have the same principal structural features) Also called GluR-1 through 4
Slide 9-

Expression patterns of AMPA receptor subunits in the brain
Slide 10-

AMPA receptor functional diversity Mixing and matching of subunits (see GABA receptors for examples) Further diversity generated by alternative splicing, editing Flip and flop splice forms desensitize at different rates, both have rapid onset kinetics (gluR2 homomers shown)
Slide 11-

Kandel, Schwartz, Jessel (2000) Principles of Neural Science 4ed Ion selectivity is modulated by RNA editing
Slide 12-

NMDA receptors
Slide 13-

NMDA receptors show slow onset and decay kinetics Some synapses have both glutamate receptor types, and produce a two-component synaptic current
Slide 14-

NMDA receptors are strongly rectifying because of Mg++ block Coincidence detector in learning and memory
Slide 15-

NMDA receptors are calcium permeable This property is particularly significant because calcium is a second messenger that plays many important regulatory roles
Slide 16-

Pharmacology AMPA agonists: AMPA, glutamate antagonists: CNQX, NBQX Kainate agonists: kainic acid, glutamate antagonist: CNQX NMDA agonists: glutamate, aspartate, NMDA antagonists: D-APV, D-AP5, MK-801, Ketamine, Phencyclidine, (Mg++)
Slide 17-

Glutamate receptors are physically tethered at synapses and associated with signaling molecules AMPA receptors interact with GRIP, SAP-97 and others Synaptic strength and Ca++ permeability of glutamate postsynaptic complexes is a major determinant of synaptic plasticity, and probably underlies learning and memory - stay tuned
Slide 18-

Inhibitory GABA presynaptic neuron excitatory presynaptic neuron inhibitory Inhibitory neurotrans-mission prevents excitation of the post-synaptic neuron
Slide 19-

Whereas glutamate is the principal excitatory neurotransmitter, GABA is the principal inhibitory neurotransmitter in the brain A typical GABA presynaptic terminal
Slide 20-

GABA synthesis Biosynthetic enzyme: GAD65, GAD67 GAD65 more highly enriched in nerve terminals, therefore might be more important for neurotransmission GAD requires pyridoxal phosphate as cofactor (might be regulated by GABA and ATP)
Slide 21-

GABA release, reuptake Vesicular release is the major mechanism Uptake is mediated by plasma membrane transporters GAT-1, GAT-2, GAT-3, BGT-1 GAT1-3 in brain, BGT-1 in kidney but may also be in brain
Slide 22-

Degradation GABA aminotransferase (aka GABA transaminase or GABA T) Astrocytes and neurons, mitochondrial
Slide 23-

Summary of GABA synthesis, release, reuptake, degradation GABA is formed by removal of carboxyl group of glutamate, by the enzyme GAD GABA is packaged into synaptic vesicles by VIAAT and released by depolarization GABA may be taken up by nerve terminal by GAT proteins for repackaging into synaptic vesicles GABA may be taken up by glial cells, where it undergoes reconversion to glutamate (amine group is transferred to -ketoglutarate, generating glutamate and succinic semialdehyde) Glutamate is transported back into nerve terminal, where it serves as precursor for new GABA synthesis
Slide 24-

GABA receptors: Fast GABA transmission mediated mainly by GABAA receptors, which are ligand-activated chloride channels. Some fast GABA transmission mediated by so-called GABAC receptors, which are a closely-related sub-family of GABAA receptors GABA also utilizes a metabotropic receptor called the GABAB receptor, described in Neuromodulation section.
Slide 25-

GABAA receptors belong to the ‘ligand-gated ion channel superfamily’, which also includes nicotinic acetylcholine receptors, glycine receptors, and the 5-HT3 serotonin receptor. Fine structure and function of this receptor class will be covered in more detail in the acetylcholine section, upcoming.
Slide 26-

GABAA receptors are heteromultimers subunits -Alpha (1-6) -Beta (1-4) -Gamma (1-4) -delta, epsilon, pi, theta -Rho (1-3) - make up the GABAC receptor Potentially thousands of different subunit combin-ations, or subtypes. Which really occur in the brain? About 12 subtypes are prevalent Bowery et al. 2002 Pharmacological Reviews 54: 247-264 McKernan and Whiting (1996) TINS 19:139-143
Slide 27-

What is the significance of this receptor diversity? Different subunit combinations (receptor subtypes) confer different functional properties. Those properties allow the receptors to do different jobs 122 EC50=13 M, fast desensitization G G 62 EC50=0.27 M, no desensitization GABA terminal Postsynaptic membrane Low GABA sensitivity of and fast desensitization 122 are suited for phasic activity and high GABA concentrations found right at the synapse. High GABA sensitivity and lack of desensitization allows 62 to detect GABA that spills over from the active synaptic zone
Slide 28-

Phasic synaptic GABA response Extrasynaptic ‘tonic’ response Inhibitor of all GABAA receptors, eliminates both phasic and tonic responses, showing that they are both GABA currents Recording from cerebellar granule cells, showing both synaptic and extrasynaptic GABA responses Extrasynaptic tonic currents are dependent on the presence of an intact 6 subunit gene
Slide 29-

GABAA receptor tethering at the synapse Several proteins that are important for GABAA receptor tethering have been proposed, principally ‘gephyrin’, but the tethering mechanism is not well characterized.
Slide 30-

GABAA receptor pharmacology Antagonists: Bicucculine competitive SR95531 (gabazine) competitive Picrotoxin mixed competitive, non-competitive Penicillin G open channel block Pentelenetetrazole (PTZ) open channel block Pregnenolone sulfate non-competitive Agonist: Muscimol Barbiturates, neurosteroids (high concentrations) Enhancers: Benzodiazepines Barbiturates, neurosteroids (low concentrations) GABAA receptor antagonists are important research tools, but not clinically useful. GABAA receptor enhancement, but not direct agonism, is useful therapeutically in neurology.
Slide 31-

Glycine neurotransmission
Slide 32-

GCS: glycine cleavage system Consists of 4 proteins T protein L protein H protein P protein Summary of GABA synthesis, release, reuptake, degradation Glycine is synthesized from serine by SHMT Glycine is packaged into synaptic vesicles by VIAAT (same transporter as for GABA) Glycine is removed from synapse by GLYT1 (glial, for clearance from synapse), and GLYT2 (neuronal, for re-uptake and packaging). Glycine is cleaved by the glycine cleavage system
Slide 33-

Glycine neurotransmission: receptors Glycine is a neurotransmitter in its own right Distinct from NMDA receptor co-agonist role Ionotropic receptor, ligand-gated ion channel superfamily receptors, homologous to GABAA receptors 1-4, subunits -  homomers in early development,  heteromers in adults Major spinal cord inhibitory transmitter Retinal, brainstem as well No allosteric regulators used as drugs Strychnine is a competitive antagonist Human mutations in glyR found in startle disease, hyperekplexia, ‘Jumping Frenchman disease’
Slide 34-

Acetylcholine neurotransmission Acetylcholine synthesized from choline and acetyl CoA by choline acetyltransferase (ChAT) ACh loaded into synaptic vesicles by VAchT Released ACh broken down by acetylcholinesterase (notable difference from other neuro-transmitters discussed so far) Choline taken up by presynaptic terminal as precursor to further ACh synthesis
Slide 35-

Nicontinic acetylcholine receptors Fast ACh neurotransmission utilizes ligand-gated ion channel superfamily receptors sensitive to nicotine, hence called nicotinic ACh receptors Muscle nAChRs: 2, , ,  subunits in the ratio of 2::: Neuronal nAChRs: 3:2 or 7 homomers
Slide 36-

nAChR characteristics Non-selective cation channels, therefore excitatory Muscle receptors localized at end plates, postsynaptic to the motor neurons, cause muscle excitation (see Control of Movement lectures) Neuronal receptors localized on presynaptic terminals, modulate the release of other neurotransmitters Agonists: Nicotine Antagonists: -bungarotoxin, -tubocurarine (muscle)
Slide 37-

Electron micrograph of nicotinic acetylcholine receptor
Slide 38-

Structure determined by cryo-EM to 4 Angstroms. Helix arrangement correct Miyazawa et al. 2003 Nature 423:949-955 Structure in greater detail
Slide 39-

Side view Top view, closed Top view, open Helices rotate Kinked M2 helix Molecular interactions underlying LGIC superfamily receptor activation (i.e. GABAA, glycine, nAChR) Kash et al. (2003) Nature 421:272-275 Lee and Sine (2005) Nature 438, 243-247
Slide 40-

Synaptic physiology and integration Textbook p.107-117
Slide 41-

EPC = gACh(Vm-Erev) Since EPCs reverse at about 0 mV, ACh channels must be equally permeable to Na+ and K+
Slide 42-

ppt slide no 42 content not found
Slide 43-

GABA neurotransmission will drive membrane potential toward the Cl- reversal potential
Slide 44-

GABA can depolarize cells depending on the direction of the chloride gradient (i.e. ECl may be suprathreshold)
Slide 45-

Summation of postsynaptic membrane potentials allows multiple synaptic inputs to be integrated