Why is the adrenal adrenergic?

The adrenal gland is the body's primary source for epinephrine production and release, and the chromaffin cells that comprise the adrenal medulla possess all of the catecholamine biosynthetic machinery, including phenylethanolamine N-methyltransferase (PNMT), the enzyme synthesizing epinephrine from norepinephrine. In most species, epinephrine, also known as adrenaline, is the predominant neurotransmitter/neurohormone expressed by chromaffin cells. Present knowledge about "what makes the adrenal adrenergic" is derived from studies of normal and neoplastic adrenal medullary tissue and cells, with the PNMT gene serving as a marker of adrenergic function. The preference for adrenergic expression occurs, in part, because of the juxtaposition of adrenal medulla and adrenal cortex, as the cortex provides high circulating levels of glucocorticoids to the medulla. However, although glucocorticoids and the activated glucocorticoid receptor clearly are critical elements, they are apparently not the sole components defining the adrenergic phenotype. Other factors may include several transcriptional activators of the PNMT gene: Egr-1, AP2, Sp1, and MAZ. The existence of transcription factors that silence PNMT expression in noradrenergic cells has also been postulated. Understanding the requirements for adrenergic expression may provide important insights and potential therapies for disorders in which adrenergic/catecholaminergic dysfunction leads to illnesses refractory to present treatment strategies.