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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
The Synapse – Signal Transduction
Loewi’s experiment demonstrating chemical neurotransmission
Cell Signaling Mechanisms
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
GABAA GABAB IL-1 Testosterone
Glycine α, β-adrenergic BDNF Glucocorticoid
5-HT3 Dopamine GDNF Mineralocorticoid
Opioid FGF
Prostaglandins CNTF
VEGF
Categories of Cellular Receptors
Types Of Neurotransmitter-Regulated Channels
• Transmitter-Gated Channels • G-protein-coupled Channels
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…
Types of GTP-Binding Protein I. Heterotrimeric G Proteins
Structure of Metabotropic Receptors
G-Protein Coupled Receptors (GPCRs)
• Receptor has 7 trans-membrane regions
• G-protein has three subunits
(heterotrimer)
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
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
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
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…
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…
Example Of G-Proteins And Adenylyl Cyclase System
Protein kinase activation - PKA
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
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
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
Ca++/Calmodulin Kinase II
Regulation of Gene Transcription by CREB
Neurotransmitters
– Structure – Synthesis – Storage and release – Degradation – Receptors
Transduction Systems
G-protein Coupled Receptor (GPCR) Signaling
• Neurotransmitter • Receptor • G-Protein • Effector Protein • Second Messengers • “Later” Effectors • Target Action
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