Pituitary adenylate cyclase-activating polypeptide (PACAP) stimulates the oxygen sensing type I (glomus) cells of rat carotid bodies via reduction of a background TASK-like K+ current.
Pituitary adenylate cyclase-activating polypeptide (PACAP)-deficient mice are prone to sudden neonatal death and have reduced respiratory response to hypoxia. Here we found that PACAP-38 elevated cytosolic [Ca(2+)] ([Ca(2+)](i)) in the oxygen sensing type I cells but not the glial-like type II (sustentacular) cells of the rat carotid body. This action of PACAP could not be mimicked by vasoactive intestinal peptide but was abolished by PACAP 6-38, implicating the involvement of PAC(1) receptors. H89, a protein kinase A (PKA) inhibitor attenuated the PACAP response. Simultaneous measurement of membrane potential and [Ca(2+)](i) showed that the PACAP-mediated [Ca(2+)](i) rise was accompanied by depolarization and action potential firing. Ni(2+), a blocker of voltage-gated Ca(2+) channels (VGCC) or the removal of extracellular Ca(2+) reversibly inhibited the PACAP-mediated [Ca(2+)](i) rise. In the presence of tetraethylammonium (TEA) and 4-aminopyridine (4-AP), PACAP reduced a background K(+) current. Anandamide, a blocker of TWIK-related acid-sensitive K(+) (TASK)-like K(+) channel, occluded the inhibitory action of PACAP on K(+) current. We conclude that PACAP, acting via the PAC(1) receptors coupled PKA pathway inhibits a TASK-like K(+) current and causes depolarization and VGCC activation. This stimulatory action of PACAP in carotid type I cells can partly account for the role of PACAP in respiratory disorders.
Xu
Fenglian
F
Department of Pharmacology and Center for Neurosciences, 9-70 Medical Science Building, University of Alberta, Edmonton, Alberta, Canada.
Tse
Frederick W
FW
Tse
Amy
A
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002344:Carotid Body / Q000166:cytology*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006133:Growth Substances / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D009474:Neurons / Q000145:classification / Q000187:drug effects* / Q000378:metabolism; D010100:Oxygen / Q000494:pharmacology*; D018408:Patch-Clamp Techniques / Q000379:methods; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019789:Tetraethylammonium / Q000494:pharmacology
D004791:Enzyme Inhibitors; D006133:Growth Substances; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D019789:Tetraethylammonium; D010100:Oxygen; D002118:Calcium