Peptides derived from the prohormone proNPQ/spexin are potent central modulators of cardiovascular and renal function and nociception.
Computational methods have led two groups to predict the endogenous presence of a highly conserved, amidated, 14-aa neuropeptide called either spexin or NPQ. NPQ/spexin is part of a larger prohormone that contains 3 sets of RR residues, suggesting that it could yield more than one bioactive peptide; however, no in vivo activity has been demonstrated for any peptide processed from this precursor. Here we demonstrate biological activity for two peptides present within proNPQ/spexin. NPQ/spexin (NWTPQAMLYLKGAQ-NH(2)) and NPQ 53-70 (FISDQSRRKDLSDRPLPE) have differing renal and cardiovascular effects when administered intracerebroventricularly or intravenously into rats. Intracerebroventricular injection of NPQ/spexin produced a 13 ± 2 mmHg increase in mean arterial pressure, a 38 ± 8 bpm decrease in heart rate, and a profound decrease in urine flow rate. Intracerebroventricular administration of NPQ 53-70 produced a 26 ± 9 bpm decrease in heart rate with no change in mean arterial pressure, and a marked increase in urine flow rate. Intraventricular NPQ/spexin and NPQ 53-70 also produced antinociceptive activity in the warm water tail withdrawal assay in mice (ED(50)<30 and 10 nmol for NPQ/spexin and NPQ 53-70, respectively). We conclude that newly identified peptides derived from the NPQ/spexin precursor contribute to CNS-mediated control of arterial blood pressure and salt and water balance and modulate nociceptive responses.
SRI International, Menlo Park, California, USA. ltoll@tpims.org
Lawrence
L
Toll
Taline V
TV
Khroyan
Kemal
K
Sonmez
Akihiko
A
Ozawa
Iris
I
Lindberg
Jay P
JP
McLaughlin
Shainnel O
SO
Eans
Amir A
AA
Shahien
Daniel R
DR
Kapusta
D000595:Amino Acid Sequence; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D002320:Cardiovascular Physiological Phenomena / Q000187:drug effects; D006801:Humans; D007276:Injections, Intraventricular; D007668:Kidney / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008969:Molecular Sequence Data; D009479:Neuropeptides / Q000008:administration & dosage / Q000235:genetics / Q000502:physiology*; D059225:Nociception / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000235:genetics / Q000502:physiology; D036361:Peptide Hormones / Q000008:administration & dosage / Q000235:genetics / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
D009479:Neuropeptides; D010446:Peptide Fragments; D036361:Peptide Hormones; D011994:Recombinant Proteins; C550448:SPX protein, rat