title: Purinergic inhibitory regulation of murine detrusor muscles mediated by PDGFRα+ interstitial cells.
abstract: Purines induce transient contraction and prolonged relaxation of detrusor muscles. Transient contraction could be due to activation of inward currents in smooth muscle cells, but the mechanism of purinergic relaxation has not been determined. We recently reported a new class of interstitial cells in detrusor muscles and showed that these cells could be identified with antibodies against platelet-derived growth factor receptor-α (PDGFRα(+) cells). The current density of small conductance Ca(2+)-activated K(+) (SK) channels in these cells is far higher (∼100 times) than in smooth muscle cells. Thus, we examined purinergic receptor (P2Y) mediated SK channel activation as a mechanism for purinergic relaxation. P2Y receptors (mainly P2ry1 gene) were highly expressed in PDGFRα(+) cells. Under voltage clamp conditions, ATP activated large outward currents in PDGFRα(+) cells that were inhibited by blockers of SK channels. ATP also induced significant hyperpolarization under current clamp conditions. A P2Y1 agonist, MRS2365, mimicked the effects of ATP, and a P2Y1 antagonist, MRS2500, inhibited ATP-activated SK currents. Responses to ATP were largely abolished in PDGFRα(+) cells of P2ry1(-/-) mice, and no response was elicited by MRS2365 in these cells. A P2X receptor agonist had no effect on PDGFRα(+) cells but, like ATP, activated transient inward currents in smooth muscle cells (SMCs). A P2Y1 antagonist decreased nerve-evoked relaxation. These data suggest that purines activate SK currents via mainly P2Y1 receptors in PDGFRα(+) cells. Our findings provide an explanation for purinergic relaxation in detrusor muscles and show that there are no discrete inhibitory nerve fibres. A dual receptive field for purines provides the basis for inhibitory neural regulation of excitability.
authors.affiliation: Department of Physiology and Cell Biology, University of Nevada School of Medicine, 1664 N. Virginia St MS 0352, Reno, NV 89557, USA. skoh@medicine.nevada.edu.
authors.forename: Haeyeong
authors.initials: H
authors.lastname: Lee
authors.forename: Byoung H
authors.initials: BH
authors.lastname: Koh
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Peri
authors.forename: Kenton M
authors.initials: KM
authors.lastname: Sanders
authors.forename: Sang Don
authors.initials: SD
authors.lastname: Koh
mesh_terms: D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D003838:Deoxyadenine Nucleotides / Q000494:pharmacology; D004558:Electric Stimulation; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D058912:Purinergic P2Y Receptor Agonists / Q000494:pharmacology; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000502:physiology*; D058472:Receptors, Purinergic P2Y1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism; D001743:Urinary Bladder / Q000166:cytology / Q000187:drug effects / Q000502:physiology*
chemical_list: C511689:(N)-methanocarba-2MeSADP; C495475:2-iodo-N(6)-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphate; D003838:Deoxyadenine Nucleotides; D058912:Purinergic P2Y Receptor Agonists; D058921:Purinergic P2Y Receptor Antagonists; D058472:Receptors, Purinergic P2Y1; D051640:Small-Conductance Calcium-Activated Potassium Channels; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D020796:Receptor, Platelet-Derived Growth Factor alpha