Steps in Neurohumoral Transmission

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Chapter: Essential pharmacology : Autonomic Nervous System: General Considerations

The resting transmembrane potential (70 mV negative inside) is established by high K+ permeability of axonal membrane and high axoplasmic concentration of this ion coupled with low Na+ permeability and its active extrusion from the neurone.


STEPS IN NEUROHUMORAL TRANSMISSION

 

Impulse Conduction

 

The resting transmembrane potential (70 mV negative inside) is established by high K+ permeability of axonal membrane and high axoplasmic concentration of this ion coupled with low Na+ permeability and its active extrusion from the neurone. Stimulation or arrival of an electrical impulse causes a sudden increase in Na+ conductance depolarization and overshoot (reverse polarization: inside becoming 20 mV positive); K+ ions then move out in the direction of their concentration gradient and repolarization occurs. Ionic distribution is normalized during the refractory period by the activation of Na+ K+ pump. The action potential (AP) thus generated sets up local circuit currents which activate ionic channels at the next excitable part of the membrane (next node of Ranvier in myelinated fibre) and the AP is propagated without decrement.

 

Tetrodotoxin (from puffer fish) and saxitoxin (from certain shellfish) selectively abolish increase in Na+ conductance in nerve fibres and thus block impulse conduction.

 

Transmitter Release

 

The transmitter (excitatory or inhibitory) is stored in prejunctional nerve endings within ‘synaptic vesicles’ (Fig. II.2). Nerve impulse promotes fusion of vesicular and axonal membranes through Ca2+ entry which fluidizes membranes. All contents of the vesicle (transmitter, enzymes and other proteins) are extruded (exocytosis) in the junctional cleft.



 

A number of proteins like synaptotagmin, synaptobrevin, neurexin, syntaxin and synaptophysin located on the vesicular and axonal membranes have been found to participate in the docking and fusion of the synaptic vesicles with the axonal membrane resulting in exocytosis. These proteins can be targets of drug action to modify junctional transmission.

 

The release process can be modulated by the transmitter itself and by other agents through activation of specific receptors located on the prejunctional membrane, e.g. noradrenaline (NA) release is inhibited by NA (α2 receptor), dopamine, adenosine, prostaglandins and enkephalins while isoprenaline (β2 receptor) and angiotensin (AT1 receptor) increase NA release. Similarly, α2 and muscarinic agonists inhibit acetylcholine (ACh) release at autonomic neuroeffector sites (but not in ganglia and skeletal muscles).

 

Transmitter Action On Postjunctional Membrane

 

The released transmitter combines with specific receptors on the postjunctional membrane and depending on its nature induces an excitatory postsynaptic potential (EPSP) or an inhibitory postsynaptic potential (IPSP).

 

EPSP Increase in permeability to all cations Na+ or Ca2+ influx (through fast or slow channels) causes depolarization followed by K+ efflux. These ionic movements are passive as the flow is down the concentration gradients.

 

IPSP Increase in permeability to smaller ions, i.e. K+ and Cl¯ (hydrated K+ ion is smaller than hydrated Na+ ion) only, so that K+ moves out and Cl¯ moves in (in the direction of their concentration gradients) resulting in hyperpolarization.

 

In addition, a trophic influence on junctional morphology and functional status is exerted by the background basal release of the transmitter.

 

Postjunctional Activity

 

A suprathreshold EPSP generates a propagated postjunctional AP which results in nerve impulse (in neurone), contraction (in muscle) or secretion (in gland). An IPSP stabilizes the postjunctional membrane and resists depolarizing stimuli.

 

Termination Of Transmitter Action

 

Following its combination with the receptor, the transmitter is either locally degraded (e.g. ACh) or is taken back into the prejunctional neurone by active uptake or diffuses away (e.g. NA, GABA). Specific carrier proteins like norepinephrine transporter (NET), dopamine transporter (DAT), serotonin transporter (SERT) are expressed on the axonal membrane for this purpose. The rate of termination of transmitter action governs the rate at which responses can be transmitted across a junction (1 to 1000/sec).

 

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