Catecholamine storage vesicles: role of core protein genetic polymorphisms in hypertension

Abstract

Hypertension is a complex trait with deranged autonomic control of the circulation. The sympathoadrenal system exerts minute-to-minute control over cardiac output and vascular tone. Catecholamine storage vesicles (or chromaffin granules) of the adrenal medulla contain remarkably high concentrations of chromogranins/secretogranins (or "granins"), catecholamines, neuropeptide Y, adenosine triphosphate (ATP), and Ca(2+). Within secretory granules, granins are co-stored with catecholamine neurotransmitters and co-released upon stimulation of the regulated secretory pathway. The principal granin family members, chromogranin A (CHGA), chromogranin B (CHGB), and secretogranin II (SCG2), may have evolved from shared ancestral exons by gene duplication. This article reviews human genetic variation at loci encoding the major granins and probes the effects of such polymorphisms on blood pressure, using twin pairs to probe heritability and individuals with the most extreme blood pressure values in the population to study hypertension.

Fig. 1

Intracellular and extracellular chromogranin/secretogranin actions. Chromaffin granule transmitter storage and exocytotic release are depicted, with secretion in response to the preganglionic transmitters acetylcholine (Ach) or pituitary adenylyl cyclase activating polypeptide (PACAP). Catestatin, the endogenous nicotinic cholinergic antagonist (ganglionic-blocking) peptide fragment of CHGA, inhibits the principal physiological trigger of chromaffin cell secretory stimulation: the nicotinic cholinergic pathway. ATP—adenosine triphosphate; CHGA—chromogranin A; CHGB—chromogranin B; nAchR—nicotinic cholinergic receptor; NPY—neuropeptide Y; PAC1R—PACAP type 1 receptor; SCG2—secretogranin II. (Adapted from Mahapatra et al. [1])

Fig. 2

Prediction of blood pressure (BP) status by CHGB promoter haplotypes in a population (of European ancestry) with BP extremes. Haplotypes (or haplotype pairs) are ordered by rank of association with elevated BP. Left: Haplotype (chromosome) effects. Right: Haplotype pair (diploid haplotype) effects. The two most common haplotypes (AA and CT) are more frequent in individuals with lower BP, whereas the two less common haplotypes (CA and AT) are more frequent in those with higher BP. CHGB—chromogranin B; HT—hypertensive; NT—normotensive. (Adapted from Zhang et al. [•])