Neurohumoral transmission involves the following four steps (figure)

Step 1: Initiation of an Action Potential and Axonal Conduction

1. During resting conditions, the membrane potential inside a typical axon is −70mV with respect to exterior of axon.
2. A high concentration of K⁺ and low levels of Na⁺ and Cl^– (K⁺ 140mM, Na⁺ 10- 15mM ) within the cell cause this difference in the resting membrane potential.
3. On the other hand, extracellularly the concentration of Na⁺ is higher than that of K⁺ (Na⁺ 140mM, K⁺ 4mM).
4. An energy-dependent active transport pump (sodium pump) maintains these ionic gradients.
5. When depolarisation reaches to threshold levels, the membrane of the neurons becomes more permeable to Na⁺ and results in a rapid depolarisation of the whole membrane.
6. Consequently, the opening of K⁺ channels is delayed, causing outflux of the K⁺ and re-polarisation of the membrane occurs.
7. Ionic currents are formed during this process resulting in the depolarisation of adjacent regions of the neural membrane. Thus, an Action Potential (AP) is propagated.

Step 2: Arrival of an AP at Nerve Terminal Resulting in the Release of the Transmitter

1. Neurotransmitters are synthesised in the nerve terminal and are stored within the synaptic vesicles.
2. As the action potential arrives at the nerve terminals, an influx of Ca²⁺ occurs to promote fusion of synaptic vesicles with adjacent axoplasmic membrane.
3. The vesicular contents are discharged (exocytosis) into the synaptic cleft and formation of new vesicles is initiated by the adjacent sections of the membrane.
4. The cell body of the neuron containing the nucleus (perikaryon) forms the site of synthesis of the neuropeptides which are then transported to the nerve terminal before being released.

Step 3: Events at the Synaptic Cleft and Postjunctional Sites

1. Diffusion of the neurotransmitter thus occurs across the synaptic cleft.
2. An interaction between the postjunctional receptors and the neurotransmitters takes place resulting in either excitatory or inhibitory postjunctional effects.
3. Excitatory Postsynaptic Potential (EPSP) occurs with the influx of Ca²⁺. Inhibitory Postsynaptic Potential (IPSP) occurs with the influx of Cl^– or outflux of K⁺ resulting in hyperpolarisation.

Step 4: Termination of Effect of Released Transmitter

1. Metabolic inactivation of the neurotransmitter by an extremely efficient enzyme, acetylcholinesterase (AChE) results in the termination at the cholinergic sites.
2. Major mechanisms involving the inactivation of the neurotransmitter takes place by enzymes Monoamine Oxidase (MAO) or catechol-o-methyl transferase (COMT) at the adrenoceptor sites.
3. Reuptake of the neurotransmitter into the nerve terminals causes the termination of neurotransmitter activity.