The granin VGF promotes genesis of secretory vesicles, and regulates circulating catecholamine levels and blood pressure.
Secretion of proteins and neurotransmitters from large dense core vesicles (LDCVs) is a highly regulated process. Adrenal LDCV formation involves the granin proteins chromogranin A (CgA) and chromogranin B (CgB); CgA- and CgB-derived peptides regulate catecholamine levels and blood pressure. We investigated function of the granin VGF (nonacronymic) in LDCV formation and the regulation of catecholamine levels and blood pressure. Expression of exogenous VGF in nonendocrine NIH 3T3 fibroblasts resulted in the formation of LDCV-like structures and depolarization-induced VGF secretion. Analysis of germline VGF-knockout mouse adrenal medulla revealed decreased LDCV size in noradrenergic chromaffin cells, increased adrenal norepinephrine and epinephrine content and circulating plasma epinephrine, and decreased adrenal CgB. These neurochemical changes in VGF-knockout mice were associated with hypertension. Germline knock-in of human VGF1-615 into the mouse Vgf locus rescued the hypertensive knockout phenotype, while knock-in of a truncated human VGF1-524 that lacks several C-terminal peptides, including TLQP-21, resulted in a small but significant increase in systolic blood pressure compared to hVGF1-615 mice. Finally, acute and chronic administration of the VGF-derived peptide TLQP-21 to rodents decreased blood pressure. Our studies establish a role for VGF in adrenal LDCV formation and the regulation of catecholamine levels and blood pressure.
1Department of Neuroscience, Box 1065, Ichan School of Medicine at Mt. Sinai, 1 Gustave L. Levy Pl., New York, NY 10029, USA. stephen.salton@mssm.edu.
Samira
S
Fargali
Angelo L
AL
Garcia
Masato
M
Sadahiro
Cheng
C
Jiang
William G
WG
Janssen
Wei-Jye
WJ
Lin
Valeria
V
Cogliani
Alice
A
Elste
Steven
S
Mortillo
Cheryl
C
Cero
Britta
B
Veitenheimer
Gallia
G
Graiani
Giulio M
GM
Pasinetti
Sushil K
SK
Mahata
John W
JW
Osborn
George W
GW
Huntley
Greg R
GR
Phillips
Deanna L
DL
Benson
Alessandro
A
Bartolomucci
Stephen R
SR
Salton
D000313:Adrenal Medulla / Q000378:metabolism; D000802:Angiotensin Amide / Q000097:blood; D000818:Animals; D001794:Blood Pressure; D019439:Chromaffin Cells / Q000378:metabolism; D053379:Chromogranin A / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004837:Epinephrine / Q000097:blood; D055879:Gene Knock-In Techniques; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D009414:Nerve Growth Factors; D009479:Neuropeptides / Q000235:genetics* / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D010641:Phenotype; D022142:Secretory Vesicles / Q000378:metabolism*
D053379:Chromogranin A; D009414:Nerve Growth Factors; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D010446:Peptide Fragments; C522412:TLQP-21 peptide; C512697:Vgf protein, mouse; D000802:Angiotensin Amide; D004837:Epinephrine
CG; LDCV; adrenal; chromaffin granule; large dense core vesicle; norepinephrine