Synaptic Transmission I: Indirect (Metabotropic) Transmission & Neuromodulation

Metabotropic receptors (GPCRs) have:

7 transmembrane domains (serpentine receptors) and act through G-proteins.

In G-protein activation, the α subunit exchanges:

GDP for GTP, causing dissociation of α and βγ subunits.

The α subunit inactivates itself by:

GTPase activity (dephosphorylates GTP to GDP), then recombines with βγ.

Examples of metabotropic receptors include:

Muscarinic AChR, adrenergic receptors (α,β), dopamine receptors, GABAB, metabotropic glutamate receptors, and rhodopsin.

Directly mediated synaptic potentials are always:

Increased conductance potentials (open ion channels), fast, and short duration.

Indirectly mediated synaptic potentials can be:

Increased OR decreased conductance (open OR close ion channels), slow, long-lasting.

Gs (G stimulatory) stimulates:

Adenylyl cyclase (increases cAMP).

Gi (G inhibitory) inhibits:

Adenylyl cyclase (some activate phospholipase C).

Gq activates:

Phospholipase C (produces IP3 and DAG).

Gk activates:

K+ channels (subset of Gi family).

Gt (transducin) activates:

cGMP phosphodiesterase (decreases cGMP; retinal photoreceptors).

Cholera toxin:

Irreversibly activates Gs (bypasses receptor), stimulating cAMP production.

Pertussis toxin:

Irreversibly inactivates Gi (and Gt), preventing inhibition of cAMP.

GTPγS (non-hydrolyzable GTP analog):

Activates G proteins irreversibly (prolongs responses).

GDPβS (GDP analog):

Inactivates G proteins (inhibits G protein-mediated responses).

G proteins can directly modulate ion channels (e.g.):

ACh activates K+ channels in cardiac muscle via Gi, and inhibits Ca2+ channels.

G proteins can act through second messengers (e.g.):

β-adrenergic receptors increase cAMP, which phosphorylates Ca2+ channels (increasing ICa in cardiac muscle).

Neuromodulation is:

The ability of synaptic or hormonal stimuli to alter active electrical behavior via intracellular biochemical changes (with or without a PSP).

Three neuronal properties affected by neuromodulation are:

1) Shape (amplitude/duration) of APs; 2) Control of spontaneous discharge; 3) Control of synaptic efficacy.

Narrowing action potentials (e.g., enkephalins on chick DRG neurons) decreases:

Transmitter release (by decreasing Ca2+ influx via Gi and PKC).

Broadening action potentials (e.g., β-adrenergic stimulation in cardiac muscle) increases:

Ca2+ influx (via Gs-cAMP-PKA), increasing force of contraction.

Noradrenaline (NA) reduces spike accommodation in hippocampal pyramidal cells by:

Inhibiting calcium-activated K+ current (IAHP), decreasing the slow AHP (via β1 adrenergic receptors).

Serotonin (5-HT) can enable plateau potentials in spinal motor neurons by:

Reducing calcium-activated K+ current, allowing L-type Ca2+ channels to maintain depolarization (bistability).

Bursting neurons (e.g., Aplysia R15) exhibit:

Clusters of APs interrupted by silent periods, driven by membrane potential oscillations.

5-HT modulates Aplysia R15 bursting by:

Increasing both the interburst hyperpolarization (via IK(IR)) and the burst depolarization (via ICa), increasing peptide secretion.