CNS

Action Potential
&
Neurotransmission
Dr. Syed Muneeb Anjum
Learning Objectives
◼ At the end of this session YOU will be able to
❑ Identify Types of Neurons & Synapse, Describe phases of AP
❑ Identify the major types of voltage-gated and ligand-gated ion
channels in neuronal membranes
❑ List the criteria for accepting a chemical as a neurotransmitter
❑ Classify the neurotransmitters
❑ List the major excitatory & Inhibitory central neurotransmitters
❑ Identify the major receptor subtypes of CNS neurotransmitters
ORGANIZATION OF THE CNS
◼ CNS Composition
❑ Brain and spinal cord
◼ Responsible for integrating sensory information
◼ Generating motor output and other behaviours
❑ Successful interaction with the environment and enhance species survival
❑ The human brain
◼ About 100 billion interconnected neurons
◼ Surrounded by various supporting glial cells
❑ Nuclei of neurons
◼ In the CNS, neurons are clustered into groups called nuclei
❑ Layers of neurons
◼ Layered structures such as the cerebellum or hippocampus
❑ Connections among neurons both within and between these clusters form
the circuitry that regulates information flow through the CNS.
Neurons
◼ Electrically excitable cells
❑ Process and transmit information via an electrochemical
process
◼ Types & Classification
❑ Many types of neurons in the CNS
❑ Classified in multiple ways:
◼ By function, by location, and by the neurotransmitter they release.
◼ The typical neuron
❑ Possesses a cell body (or soma)
❑ Specialized processes called dendrites and axons
Neurons
◼ The Dendrites
❑ Highly branched complex dendritic “trees,”
◼ Receive and integrate the input from other neurons
◼ Conduct this information to the cell body (soma)
◼ The Axon
❑ Carries the output signal of a neuron from the cell body
◼ There may be hundreds of dendrites but generally only one axon
◼ Axons may branch distally to contact multiple targets
◼ Synapse
❑ A specialized junction where the axon terminal makes
contact with other neurons
◼ Here neurotransmitter chemicals are released that interact with
receptors on other neurons
A typical neuron
Neurons
Neurons & Their Types (Structure)
Neurons & Their Types (Structure)
Neurons & Their Types (Function)
Neurons & Their Types (Function)
Neurotransmission
◼ Synaptic Transmission
❑ Electrical movement within synapses caused by a
propagation of nerve impulses
◼ Neurotransmitters
❑ Chemicals secreted from the presynaptic terminal and diffuse
across the synaptic cleft binding to channels and other
molecules (receptors) in the membrane of the postsynaptic
cleft
 Synapse & Its Types
◼ Electrical Synapse
❑ Gap Junctions
❑ Fast signal transmission
❑ Fast Response
◼ Reflex Actions
❑ Blinking
❑ Ions move directly
◼ Chemical Synapse
❑ More space bw cells
❑ Neurotransmitter Req.
Chemical Synapse
Electrical Synapse
Chemical vs Electrical Synapse
Neuronal Signalling
Phases of Action Potentials (AP)
Synaptic Potentials
◼ Change in the potential, voltage, of the post synaptic cell
❑ An alteration in the membrane potential of a cell resulting from
activation of a synaptic input
◼ Excitatory Postsynaptic Potentials (EPSPs)
❑ Synaptic potential that makes a postsynaptic neuron More likely to
generate an action potential
◼ Na+ or Ca++ Influx, Inhibition of K+ efflux
◼ Inhibitory Postsynaptic Potentials (IPSPs)
❑ Synaptic potential that makes a postsynaptic neuron less likely to
generate an action potential
◼ K+ Efflux , Cl- Influx
EPSP vs IPSP
EPSPs
IPSPs
◼ Two types
❑ IPSPs
❑ Presynaptic inhibition
◼ Specialized synapse –
Axo-axonal
❑ Reduce the amount of
transmitter released from
the terminals of sensory
fibers
◼ Presynaptic inhibitory
receptor mediated
Summation
◼ Temporal
Summation
◼ Spatial
Summation
Ligand Gated Ion Channels
Molecular Targets for drug action: Cell Receptors
◼ Cell Surface Receptor
❑ GPCRs
❑ Enzyme Linked Receptors
❑ Ion Channels
◼ Voltage Gated
◼ Ligand Gated
◼ Mechanically Gated
◼ Intracellular Receptors
❑ Cytoplasmic Receptors
❑ Nuclear Receptors
Ion Channels
◼ Gateways in cell membranes that selectively allow the
passage of particular ions
❑ Two types
❑ Based on the mechanisms controlling their gating
◼ opening and closing
❑ Voltage Gated
❑ Ligand Gated
Voltage Gated Ion Channels
❑ Transmembrane ion channels regulated by changes in
membrane potential
◼ Examples
❑ Voltage Sensitive Na+ Channels ----
◼ Highly concentration in initial part of axons
❑ All or nothing fast action potentials
❑ Transmission from Cell body → nerve terminal
❑ Voltage Sensitive Ca++ and K+ Channels ---
◼ Cell bodies and dendrites
◼ Slow acting & modulate neuronal discharge
❑ Acting as brake
Ligand Gated Ion Channel
❑ Transmembrane ion channels that are regulated by
interactions between neurotransmitters and their receptors
◼ Ionotropic
❑ Direct binding to ion channel
◼ Metabotropic
❑ G-protein-coupled receptors
◼ Respond to neurotransmitters either by a direct action of G proteins
on ion channels or by
◼ G-protein-enzyme activation that leads to formation of diffusible
second messengers
Metabotropic
Types of Receptor-Channel Coupling
◼ Ligand-gated ion channels Coupling
❑ Direct Coupling (membrane delimited pathway)
◼ Through a G-protein subunit (often β) that acts directly on the
channel protein
❑ Modulates the voltage sensitive ion channels
▪ Ca++ (Presynaptic)
▪ K+ (Postsynaptic)

❑ Indirect Coupling
◼ Through a receptor that is coupled to the ion channel through a G protein
◼ Through a receptor coupled to a G protein that modulates the formation of
diffusible second messengers, including
❑ Cyclic adenosine monophosphate (cAMP), (Gs and/or Gi)

❑ Inositol trisphosphate (IP 3), and diacylglycerol (DAG), (Gq)

▪ which secondarily modulate ion channels

Receptor effector linkage
 Four main types of receptors

Monomeric proteins → Single polypeptide chain → e.g. Myoglobin

Oligomeric proteins → More than one subunit (polypeptide chain) → e.g. Hemoglobin
1. Homo-oligomers (Identical copies of polypeptides) → e.g. Collagen
2. Hetero-oligomers (At least one different copy of polypeptide chain) e.g Hb
Altering functions of ion channels
◼ Drugs can affect ion channel function in several ways
❑ By binding to the channel protein itself
◼ Allosteric (Other than ligand binding sites)
1. BZPs binding to BZP receptor – different site than ligand
2. Dihydropyridine type drugs - Vasodilators – Block opening of L-Type
Ca++ Channels
3. Involving an activated G protein subunit or other intermediary – e.g.
Gβγ subunits
▪ Activate potassium channels
▪ Inhibit voltage-gated calcium channels
4. By altering the level of expression of ion channels on the cell surface
eg. Gabapentin → reduces insertion of neuronal calcium channels
◼ Orthosteric (Binding to ligand binding site of ligand-gated channel)
❑ Ach binding to Cholinergic Nicotinic Receptors
◼ Making molecular Plugs in ion channels
❑ Local anaesthetics on VG sodium channels
 FIGURE 1 | Cellular mechanisms of neuromodulation of axonal ion channels.
(A) Schematic of axon sub compartments. Sodium (NaV), potassium (KV), and calcium (CaV) permeable voltage-gated ion channels are shown in red, blue,
and green, respectively.
(B) Schematic of GPCR neuromodulation of voltage-gated ion channels in the axon initial segment. Bars or circles at end of lines indicate a net reduction or
increase, respectively, in target channel ion flux as a result of neuromodulation.
Note that inhibition of KV7 channels is a downstream consequence of CaV3.2 modulation due to changes in intracellular calcium concentration.
(C) Schematic of GPCR neuromodulation of CaV in the terminal bouton.

(D) Solid lines indicate direct binding of Gβγ subunits to CaVs, dashed lines indicate intermediate steps.
Types of G-Proteins
G-Protein Receptor for Effector / Signalling pathway
Gs β-Adrenergic Amines, Glucagon, ↑ Adenylyl cyclase →↑ cAMP
Histamine, Serotonin etc

Gi1, Gi2, Gi3 α2-Adrenergic amines, acetylcholine ↓ Adenylyl Cyclase→ ↓ cAMP

(muscarinic), opioids, serotonin Open cardiac K+ channels → ↓heart
rate

Golf Odorants (olfactory epithelium) ↑ Adenylyl cyclase →↑ cAMP

Go Neurotransmitters in brain (not yet Not yet clear
specifically identified)

Gq Acetylcholine (muscarinic), bombesin, ↑ Phospholipase C →↑ IP3, ↑DAG, ↑

serotonin (5-HT2) cytoplasmic Ca2+

Gt1, Gt2 Photons (rhodopsin and colour opsins ↑ cGMP phosphodiesterase →↓

in retinal rod and cone cells) cGMP (phototransduction)