Neuron to Neuron Communication

Neuron to Neuron Communication

• Action potential reaches the synaptic terminal, leading to local voltage changes across the membrane
• Voltage changes activate voltage-gated ion channels, resulting in an influx of calcium ions
• Calcium ions trigger the mobilization and fusion of synaptic vesicles with the cell membrane, releasing neurotransmitters into the synaptic cleft

Excitatory and Inhibitory Neurotransmission

• Glutamate activates postsynaptic ionotropic glutamate receptors, causing an excitatory postsynaptic potential (EPSP)
• GABA activates postsynaptic ionotropic GABA receptors, causing an inhibitory postsynaptic potential (IPSP)

Ionotropic Receptors

• Ionotropic receptors are ligand-gated ion channels, also known as neurotransmitter receptors
• Neurotransmitter binding causes a conformational change, opening the ion channel
• Examples: ionotropic glutamate receptors and ionotropic GABA receptors

Metabotropic Receptors

• Metabotropic receptors have one subunit with 7 transmembrane alpha helices (TM 1-7)
• The cytoplasmic loops interact with G proteins
• Examples: muscarinic acetylcholine receptors, adrenergic receptors, and metabotropic glutamate receptors

Metabotropic Glutamate Receptors (mGluRs)

• mGluRs of groups II and III are predominantly expressed on the presynaptic side, negatively linked to transmitter release
• mGluRs of group I are found postsynaptically
• Activation of presynaptic mGluRs increases transmitter release, requiring arachidonic acid as a co-transmitter

Ionotropic Glutamate Receptors

• Glutamate is the primary excitatory neurotransmitter in the mammalian brain
• AMPA and NMDA-type glutamate receptors are the main receptors involved
• NMDA receptors have a Mg2+ block, and their Ca2+ permeability is important for synaptic plasticity

Ionotropic Glutamate Receptor Structure

• Four transmembrane alpha helices (M1-M4)
• The Glu binding domain is encoded on the N-terminal
• The channel is formed by four subunits, surrounding the pore of the channel
• When open, the ion channel is permeable to Na+, K+, and in some cases, Ca2+

AMPA and NMDA Receptors

• AMPA receptors: fast sodium entry, fast EPSP, fast inactivation
• NMDA receptors: slow activation, Ca2+ permeability, stay open for a long time
• NMDA receptors require co-activators: glycine and D-serine

NMDA Receptor Kinetics

• Glycine (together with glutamate) is required for the activation of NMDA receptors
• NMDA receptors are readily blocked by magnesium (Mg2+)
• Ketamine selectively blocks NMDA channels

Molecular Integrators

• NMDA receptors act as molecular integrators, opening only when the membrane is already depolarized by AMPA receptors
• This allows Ca2+ to enter the cell, leading to synaptic plasticity, memory, long-term potentiation, and neuronal death

GABA Receptors

• GABA is the main inhibitory neurotransmitter in the vertebrate brain
• GABA binds to GABAA receptors with high affinity
• GABAA receptors have a pentameric structure with 5 subunits, an allosteric binding site for GABA, and a benzodiazepine binding site between alpha and gamma subunits

GABA Functions

• GABA(A) receptors contribute to several components of the anaesthetic state, including amnesia, sedation, hypnosis, and immobility
• GABA(A) receptors are substrates for some general anaesthetics

Propofol

• Propofol is frequently used for the induction of anaesthesia
• Propofol works by increasing GABA-mediated inhibition, decreasing the rate of dissociation of GABA from the GABAA receptor, leading to longer-lasting hyperpolarization of cell membranes