Peptidergic G Protein–Coupled Receptor Regulation of Adrenal Function: Bench to Bedside and Back

An altered secretion of adrenocortical and adrenomedullary hormones plays a role in the clinical syndromes of primary aldosteronism (PA), Cushing's and pheochromocytoma. Moreover, an altered production of adrenocortical hormones and/or an abnormal release of factors by the adrenal medulla are involved in several other diseases, including high blood pressure, congestive heart failure, liver cirrhosis, nephrotic syndrome, primary reninism, renovascular hypertension, Addison's disease, Bartter's, Gitelman's syndromes, and virilization syndromes. Understanding the regulation of adrenal function and the interactions between adrenal cortex and medulla is, therefore, the prerequisite for mechanistic understanding of these disorders. Accumulating evidences indicate that the modulation of adrenal hormone biosynthesis is a process far more complex than originally thought, as it involves several factors, each cooperating with the others. Moreover, the tight vascular and neural interconnections between the adrenal cortex and medulla underlie physiologically relevant autocrine/paracrine interactions involving several peptides. Besides playing a patho-physiological role in common adrenal diseases, these complex mechanisms could intervene also in rare diseases, such as pheochromocytoma concomitant with adrenal Cushing or with primary aldosteronism, and primary aldosteronism co-occurring with Cushing, through mechanisms that remain to be understood at the molecular levels. Heterodimerization of G protein-coupled receptors induced by peptide signaling is a further emerging new modulatory mechanism capable of finely tuning adrenal hormones synthesis and release. In this review we will examine current knowledge on the role of peptides that act via G protein-coupled receptors in the regulation of adrenal hormones secretion with a particular focus on autocrine-paracrine signals.