Mechanism of action of catestatin as an autocrine modulator regulating catecholamine secretion from chromaffin cells at the of splanchnicoadrenomedullary synapse

Objective The chromogranin A (CgA)‐derived peptide catestatin (CST: human CgA 352–372 ) is thought to act as an autocrine modulator of catecholamine secretion from the adrenal medulla in vivo. Here, we examined how CST affects nicotine‐ and PACAP‐induced secretion from, and protein resynthesis within, dense core (DC) vesicle (DCV) quanta containing catecholamines and chromogranin/secretogranin proteins in PC12 cells. Methods and Results Depletion of norepinephrine (NE) from PC12 cells treated acutely (0.5 hours) with either nicotine (60 μM)‐ or PACAP (0.1 μM) was reversed by CST (2 μM), as was 3 H‐NE release elicited by both secretagogues. DCV and DC area and diameter, evaluated by Transmission Electron Microscopy, were both decreased after treatment with either nicotine or PACAP, and this morphological effect was likewise reversed by CST. Nicotine or CST alone increased expression of CgA protein (but not CgB), and, in combination, elicited an additional increase in CgA protein, implying that nicotine and CST utilize separate signaling pathways to activate expression of CgA. In contrast, PACAP increased expression of CgB protein (but not CgA), indicating differential regulation of CgA and CgB proteins by cholinergic and peptidergic stimulation. Although CST augmented expression of tyrosine hydroxylase (TH) protein, it did not induce synthesis of catecholamines, presumably due to its inability to cause post‐translation activation of TH via serine phosphorylation. Increased area and diameter of DCVs, and their DCs after CST, CST+nicotine and CST+PACAP are consistent with increased quantal size. Decreased quantal size is possibly mediated by increased synthesis of granulogenic proteins: CgA after CST treatment; CgA after CST+nicotine treatment; and CgB after CST+PACAP treatment. Conclusion Based on our results obtained in PC12 cells, we suggest that the CgA‐derived peptide CST acts as a paracrine factor during ACh or PACAP stimulation of secretion from chromaffin cells of the adrenal medulla, modulating both the extent of secretory stimulation by splanchnic nerve firing, and the repletion of secretory granule content after bouts of secretory activity. Support or Funding Information Supported by grants from the VA (I01BX000323 to S.K.M.; I01BX002709 to N.J.G.W), and the NIH (MH002386 to L.E.E.). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .