Inositol triphosphate-mediated Ca2+ signals direct purinergic P2Y receptor regulation of neuronal ion channels.
Purinergic P2Y receptors are one of four types of G(q/11)-coupled receptors in rat superior cervical ganglia (SCG) sympathetic neurons. In cultured SCG neurons, purinergic and bradykinin suppression of I(M) were similar in magnitude and somewhat less than that by muscarinic agonists. The effects of the P2Y receptor agonist UTP on neuronal excitability and discharge properties were studied. Under current clamp, UTP increased action potential (AP) firing in response to depolarizing current steps, depolarized the resting potential, decreased the threshold current required to fire an AP, and decreased spike-frequency adaptation. These effects were very similar to those resulting from bradykinin stimulation and not as profound as from muscarinic stimulation or full M-current blockade. We then examined the P2Y mechanism of action. Like bradykinin, but unlike muscarinic, purinergic stimulation induced rises in intracellular [Ca(2+)](i). Tests using expression of IP(3)"sponge" or IP(3) phosphatase constructs implicated IP(3) accumulation as necessary for purinergic suppression of I(M). Overexpression of wild-type or dominant-negative calmodulin (CaM) implicated Ca(2+)/CaM in the purinergic action. Both sets of results were similar to bradykinin, and opposite to muscarinic, suppression. We also examined modulation of Ca(2+) channels. As for bradykinin, purinergic stimulation did not suppress I(Ca), unless neuronal calcium sensor-1 (NCS-1) activity was blocked by a dominant-negative NCS-1 construct. Our results indicate that P2Y receptors modulate M-type channels in SCG cells via IP(3)-mediated [Ca(2+)](i) signals in concert with CaM and not by depletion of phosphatidylinositol-4, 5-biphosphate. We group purinergic P2Y and bradykinin B(2) receptors together as having a common mode of action.
Zaika
Oleg
O
Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
Tolstykh
Gleb P
GP
Jaffe
David B
DB
Shapiro
Mark S
MS
D000818:Animals; D000831:Animals, Newborn; D000873:Anthracenes / Q000494:pharmacology; D001920:Bradykinin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D003198:Computer Simulation; D004307:Dose-Response Relationship, Radiation; D004558:Electric Stimulation / Q000379:methods; D015544:Inositol 1,4,5-Trisphosphate / Q000494:pharmacology; D007295:Inositol Phosphates / Q000494:pharmacology*; D007473:Ion Channels / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000528:radiation effects; D008959:Models, Neurological; D009474:Neurons / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D018048:Receptors, Purinergic P2 / Q000502:physiology*; D017783:Superior Cervical Ganglion / Q000166:cytology; D014544:Uridine Triphosphate / Q000494:pharmacology
C112297:10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone; D000873:Anthracenes; D007295:Inositol Phosphates; D007473:Ion Channels; D018048:Receptors, Purinergic P2; D015544:Inositol 1,4,5-Trisphosphate; D001920:Bradykinin; D002118:Calcium; D014544:Uridine Triphosphate
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