Figure 2.

Chromaffin cell activation, signalling, and catecholamine release. Following activation of adrenal SPN by stimulus, acetylcholine and PACAP are released from the SPN nerve terminals in the synapse and bind to nAChR and PAC1 receptors, respectively, on the surface of chromaffin cells. Acetylcholine (Ach) is the primary neurotransmitter and causes cell depolarisation, opening of the voltage-gated calcium channels, and calcium entry followed by calcium-dependent exocytosis of catecholamines (CAs). The influx of calcium also stimulates various signaling pathways to increase tyrosine hydroxylase phosphorylation (pTH) and activation, and CA synthesis to replenish the released CAs. PACAP is another major neurotransmitter found in the adrenal SPNs but unlike Ach, it causes only a minor cellular depolarisation, and the resulting calcium entry of a low magnitude. Activation of PAC1 receptors, in association with adenyl cyclase (AC) by PACAP leads to cAMP-dependent activation of PKA, leading to the activation of CREB/AP1 and consequent induction of TH and neuropeptide mRNA levels. The newly synthesised neuropeptides are packaged into vesicles and co-released together with CAs in the bloodstream upon demand. Adrenal SPNs also contain a variety of other neuropeptides; however, their role in response to stress is still to be established. SPN, sympathetic preganglionic neurons; PACAP, pituitary adenylate cyclase-activating polypeptide; nAChR, nicotinic acetylcholine receptors; PAC1, PACAP type 1; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; PKC, protein kinase C; MEK/ERK, mitogen-activated protein kinase/extracellular signal-related kinase/; CREB, cyclic amp-response element binding protein; AP1, activator protein 1; CaM—PKII, Ca2+/calmodulin—protein dependent kinase II.