Location, Development, Control, and Function of Extraadrenal Phenylethanolamine N‐Methyltransferase

Abstract

Phenylethanolamine N-methyltransferase (PNMT) methylates norepinephrine (NE) to form epinephrine (E). It is present in a high concentration in the adrenal medula but occurs in many other tissues throughout the body. In the brain stem and retina PNMT is present in specific neurons. Cardiac PNMT develops early in the fetal heart and is found in relatively high levels in the adult left atrium. Intrinsic cardiac adrenergic cells are distributed throughout the adult myocardium and contain all the enzymes necessary for E synthesis. The PNMT gene promoter region contains a glucocorticoid response element; however, the initial development of brain and cardiac fetal PNMT is glucocorticoid independent. Rat fetal heart PNMT peaks at embryonic day 11 and becomes sensitive to glucocorticoid induction by day 12. PNMT-containing cells are concentrated in the atrioventricular canal and interventricular septum during cardiac development, areas important in the development of the cardiac conduction system. In the adult rat, cardiac PNMT is inducible by glucocorticoids and synthesizes E. Glucocorticoids are essential for development of the high levels of PNMT in the adrenal, but are less important outside the adrenal. The PNMT gene contains 3 exons and 2 introns. Adrenal PNMT mRNA exists as a single type, but in the heart PNMT mRNA is present as both an intronless and an intron-containing type. In some cardiac tissues, glucocorticoids decrease levels of intron-containing PNMT mRNA and increase intronless PNMT mRNA and PNMT activity. Studies in adrenalectomized animals suggest that extraadrenal PNMT increases blood pressure, blood glucose, and lymphocyte cytokine production. PNMT may also play a role in the regulation of fetal heart rate prior to development of the adrenal medulla.

Mutations in human monoamine-related neurotransmitter pathway genes

“…PNMT is present in many tissues throughout the body, with particularly high concentrations in the adrenal medulla and the left atrium of the heart [Ziegler et al, 2002]. Its product epinephrine plays an important role for adrenergic control of stress, metabolic function, and energy metabolism [Goldstein, 1995].…”

Epinephrine Is Required for Normal Cardiovascular Responses to Stress in the Phenylethanolamine N-Methyltransferase Knockout Mouse

“…Second, the adrenal medulla releases not only EPI but also NE, chromogranin A, catestatin, pancreastatin, neuropeptide Y, and other hormones. Third, EPI synthesis is concentrated in the adrenal medulla but also is present in many adult tissues outside the adrenal such as heart [15][16][17] and blood vessels. 18 These peripheral tissues might make enough EPI to tonically stimulate adrenergic receptors locally because EPI is a potent agonist of adrenergic receptors, especially the ␤ 2 -adrenergic receptor, for which it has a much higher affinity than any other known endogenous compound.…”

Regulation of the Rat PhenylethanolamineN-Methyltransferase Gene by Transcription Factors Sp1 and MAZ

“…Recently, two forms of PNMT mRNA were identified in PC-12 cells in vitro and mouse heart in vivo (Unsworth et al, 1999;Ziegler et al, 2002). The difference between these variants lies in post-transcriptional processing; the longer of the two forms is intron-retaining PNMT mRNA and the shorter form is intronless PNMT mRNA.…”

“…Although both MAZ and Sp1 activate the PNMT promoter to increase reporter gene and endogenous PNMT gene expression, we show that in the case of the endogenous PNMT gene, MAZ activation preferentially stimulates the production of an intron-retaining form of PNMT mRNA. From the latter, a truncated, enzymatically inactive PNMT enzyme is produced (Unsworth et al, 1999;Ziegler et al, 2002). In contrast, Sp1 preferentially stimulates the production of spliced, intronless PNMT mRNA from which active enzyme can be generated.…”