SITES OF CHOLINERGIC ACTION

Cholinergic Transmission: Site Differences

Skeletal Muscle

Neurotransmitter: Acetylcholine

Receptor Type: Nicotinic

Sectioning and degeneration of motor and post-ganglionic nerve fibers results in:

an enhanced post-synaptic responsiveness, denervation hypersensitivity.

Denervation hypersensivity in skeletal muscle is due to

increased expression of nicotinic cholinergic receptors

and their spread to regions aways from the endplate.

Autonomic Effectors

Neurotransmitter: Acetylcholine

Receptor type: Muscarinic

effector coupled to receptor by a G protein

In smooth muscle and in the cardiac conduction system, intrinsic electrical activity and mechanism activity is present, modifiable by autonomic tone.

Activities include propagated slow waves of depolarization: Examples: intestinal motility and spontaneous depolarizations of cardiac SA nodal pacemakers.

Acetylcholine decreases heart rate by decreases SA nodal pacemaker phase 4 depolarization.

The cardiac action potential associated with HIS-purkinje fibers or ventricular muscle consists of five phases

Phase 0 corresponds to Na+ channel activation.

The maximum upstroke slope of phase 0 is proportional to the sodium current.

Phase 0 slope is related to the conduction velocity in that the more rapid the rate of depolarization the greater the rate of impulse propagation.

Phase 1 corresponds to an early repolarizing K+ current. This current like the Phase 0 sodium current is rapidly inactivated.

Phase 2 is the combination of an inward, depolarizing Ca2+ current balanced by an outward, repolarizing K+ current (delayed rectifier).

Phase 3 is also the combination of Ca2+ and K+ currents.

Phase 3 is repolarizing because the outward (repolarizing) K+ current increases while the inward (depolarizing) Ca2+ current is decreasing.

Phase 4 in normal His-Purkinje and ventricular muscle cells is characterized by a balance between outward Na+ current and inward K+ current. As a result, the membrane potential would normally be flat.

In disease states or for other cell types (SA nodal cells) the membrane potential drifts towards threshold. This phenomenon of spontaneous depolarization is termed automaticity and has an important role in arrthymogenesis.

Rate of phase 4 depolarization is decreased by an increase in K+ conductance--which leads to membrane hyperpolarization (takes longer to reach threshold)

Autonomic Ganglia
Neurotransmitter: Acetylcholine
Receptor type: Nicotinic
Generally similar to skeletal muscle site: initial depolarization is due to receptor activation. The receptor is a ligand-gated channel.
Blood vessels
Choline ester administration results in blood vessel dilatation as a result of effects on prejunctional inhibitory synapses of sympathetic fibers and inhibitory cholinergic (non-innervated receptors).
In isolated blood vessel preparations, acetycholine's vasodilator effects are mediated by activation of muscarinic receptors which cause release of nitric oxide, which produces relaxation.
Signal Transduction

Nicotinic Receptors

Ligand-gated ion channels

Agonist effects blocked by tubocurarine

Receptor activation results in:

rapid increases of Na+ and Ca2+ conductance

deplorization

excitation

Subtypes based on differing subunit composition: Muscle and Neuronal Classification

Muscarinic Receptors

G-protein coupled receptor system

Slower responses

Agonist effects blocked by atropine

At least five receptor subtypes have been described by molecular cloning. Variants have distinct anatomical locations and differing molecular specificities