Purinergic inhibitory regulation of murine detrusor muscles mediated by PDGFRα+ interstitial cells

• Published in: The Journal of physiology 2014-03, Vol.592 (6), p.1283-1293
• Main Authors: Lee, Haeyeong, Koh, Byoung H., Peri, Lauren E., Sanders, Kenton M., Koh, Sang Don
• Format: Article
• Language: English
• Subjects: Adenosine Diphosphate - analogs & derivatives; Adenosine Diphosphate - pharmacology; Adenosine Triphosphate - metabolism; Adenosine Triphosphate - pharmacology; Animals; Deoxyadenine Nucleotides - pharmacology; Electric Stimulation; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Muscle Relaxation - drug effects; Muscle Relaxation - physiology; Muscle, Smooth - drug effects; Muscle, Smooth - physiology; Purinergic P2Y Receptor Agonists - pharmacology; Purinergic P2Y Receptor Antagonists - pharmacology; Receptor, Platelet-Derived Growth Factor alpha - physiology; Receptors, Purinergic P2Y1 - deficiency; Receptors, Purinergic P2Y1 - genetics; Receptors, Purinergic P2Y1 - physiology; Renal and Endocrine; Small-Conductance Calcium-Activated Potassium Channels - metabolism; Urinary Bladder - cytology; Urinary Bladder - drug effects; Urinary Bladder - physiology
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2013.267989

Key points Platelet‐derived growth factor receptor‐α‐positive (PDGFRα+) interstitial cells in detrusor muscles may participate in post‐junctional responses to neurotransmitters. PDGFRα+ interstitial cells express purinergic receptors (P2Y) and small conductance Ca2+‐activated K+ channels (mainly SK3). ATP elicited large amplitude outward currents and hyperpolarization in PDGFRα+ cells. SK channel blockers and a P2Y1 receptor antagonist blocked responses to ATP. ATP elicited only minor responses in PDGFRα+ cells of P2ry1−/− mice. ATP elicited transient inward currents in smooth muscle cells and purinergic receptor (P2X) agonists had no effect on PDGFRα+ cells. A specific P2Y1 receptor blocker decreased electrical field stimulation‐induced relaxation. Our findings provide an explanation for the purinergic relaxation of detrusor muscles and describe a novel mechanism for inhibitory regulation of bladder muscles that may control detrusor excitability during the filling phase. 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 Ca2+‐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 rece