11/8/16. Cell Signaling Mechanisms. Dr. Abercrombie 11/8/2016. Principal Parts of Neurons A Signal Processing Computer

Transcription

1 Cell Signaling Mechanisms Dr. Abercrombie 11/8/2016 Principal Parts of Neurons A Signal Processing Computer A Multitude of Synapses and Synaptic Actions Summation/Synaptic Integration 1

2 The Synapse Signal Transduction Loewi s experiment demonstrating chemical neurotransmission Cell Signaling Mechanisms 2

3 Chemical Signaling Mechanisms Classes of Cell Signalling Molecules Categories of Cellular Receptors Categorization of Types of Receptors Ionotropic Metabotropic Tyrosine Kinase/ Growth Factor Hormone Nicotinic Ach Muscarinic ACh Insulin Thyroid Glutamate (NMDA) Glutamate (AMPA) NGF Estrogen GABA A GABA B IL-1 Testosterone Glycine α, β-adrenergic BDNF Glucocorticoid 5-HT 3 Dopamine GDNF Mineralocorticoid Opioid Prostaglandins FGF CNTF VEGF 3

4 Categories of Cellular Receptors Types Of Neurotransmitter-Regulated Channels Transmitter-Gated Channels G-protein-coupled Channels 4

5 Signal Amplification 1. Transmitter-gated channels are very fast 2. G-protein-gated channels permit amplification of a signal Amplification in Signal Transduction Pathways G-protein Coupled Receptor (GPCR) Signaling Neurotransmitter GPCR (GTP binding - two major types) Effector Protein adenylyl cylcase, PLC Second Messengers e.g. cyclic nucleotides, DAG/IP3, Ca++ Later Effectors ser/thr kinases, phosphatases Target Action protein phosphorylation, Ca++ binding proteins 5

6 Types of GTP-Binding Protein I. Heterotrimeric G Proteins Structure of Metabotropic Receptors G-Protein Coupled Receptors (GPCRs) Receptor has 7 transmembrane regions G-protein has three subunits (heterotrimer) 6

7 RECEPTOR CATALYZED NUCLEOTIDE EXCHANGE G-protein Cycle 1. Binding of ligand to receptor 2. GTP replaces GDP on G-protein 3. Dissociation of the G-protein into two subunits 4. Subunits can each activate various systems 5. GTP is hydrolyzed to GDP 6. Protein reform into a single unit Example of G-Protein Activation Of A Channel 7

8 Example Of G-Protein Activation Of An Enzyme G-protein Coupled Receptor (GPCR) Signaling Neurotransmitter GPCR (GTP binding - two major types) Effector Protein adenylyl cylcase, PLC Second Messengers e.g. cyclic nucleotides, DAG/IP3, Ca++ Later Effectors ser/thr kinases, phosphatases Target Action protein phosphorylation, Ca++ binding proteins Types of GTP-Binding Protein II. Monomeric G-Proteins 8

9 G-protein Coupled Receptor (GPCR) Signaling Neurotransmitter GPCR (GTP binding - two major types) Effector Protein adenylyl cylcase, PLC Second Messengers e.g. cyclic nucleotides, DAG/IP3, Ca++ Later Effectors ser/thr kinases, phosphatases Target Action protein phosphorylation, Ca++ binding proteins The mechanism of action of second messengers 9

10 Second Messengers G-protein Coupled Receptor (GPCR) Signaling Neurotransmitter GPCR (GTP binding - two major types) Effector Protein adenylyl cylcase, PLC Second Messengers e.g. cyclic nucleotides, DAG/IP3, Ca++ Later Effectors ser/thr kinases, phosphatases Target Action protein phosphorylation, Ca++ binding proteins 10

11 Gs signaling Gi Signaling G-protein Coupled Receptor (GPCR) Signaling Neurotransmitter GPCR (GTP binding - two major types) Effector Protein adenylyl cylcase, PLC Second Messengers e.g. cyclic nucleotides, DAG/IP3, Ca++ Later Effectors ser/thr kinases, phosphatases Target Action protein phosphorylation, Ca++ binding proteins 11

12 Example Of G-Proteins And Adenylyl Cyclase System Protein kinase activation - PKA 12

13 G-protein Coupled Receptor (GPCR) Signaling Neurotransmitter GPCR (GTP binding - two major types) Effector Protein adenylyl cylcase, PLC Second Messengers e.g. cyclic nucleotides, DAG/IP3, Ca++ Later Effectors ser/thr kinases, phosphatases Target Action protein phosphorylation, Ca++ binding proteins Phosphorylation state of target proteins 13

14 G-protein Coupled Receptor (GPCR) Signaling Neurotransmitter GPCR (GTP binding - two major types) Effector Protein adenylyl cylcase, Second Messengers e.g. cyclic nucleotides,, Ca++ Later Effectors ser/thr kinases, phosphatases Target Action protein phosphorylation, Ca++ binding proteins PLC mediated signal transduction Example Of G-Proteins And a PKC/Phospholipase C System 14

15 15

16 G-protein Coupled Receptor (GPCR) Signaling Neurotransmitter GPCR (GTP binding - two major types) Effector Protein adenylyl cylcase, PLC Second Messengers e.g. cyclic nucleotides, DAG/IP3, Later Effectors ser/thr kinases, phosphatases Target Action protein phosphorylation, Ca++ binding proteins Ca++ as an Intracellular Signal Ca++ as a Second Messenger 16

17 Ca++/Calmodulin Kinase II Regulation of Gene Transcription by CREB 17

18 Neurotransmitters Structure Synthesis Storage and release Degradation Receptors 18

19 Transduction Systems G-protein Coupled Receptor (GPCR) Signaling Neurotransmitter Receptor G-Protein Effector Protein Second Messengers Later Effectors Target Action 19