UTP activates small-conductance Ca²⁺-activated K⁺ channels in murine detrusor PDGFRα⁺ cells

Abstract

Purines induce transient contraction and prolonged relaxation of detrusor muscles. Transient contraction is likely due to activation of inward currents in smooth muscle cells, and prolonged relaxation may be due to activation of small-conductance Ca(2+)-activated K(+) (SK) channels via P2Y1 receptors expressed by detrusor PDGF receptor (PDGFR)α(+) cells. We investigated whether other subtypes of P2Y receptors are involved in the activation of SK channels in PDGFRα(+) cells of detrusor muscles. Quantitative analysis of transcripts revealed that P2ry2, P2ry4, and P2ry14 are expressed in PDGFRα(+) cells of P2ry1-deficient/enhanced green fluorescent protein (P2ry1(-/-)/eGFP) mice at similar levels as in wild-type mice. UTP, a P2Y2/P2Y4 agonist, activated large outward currents in detrusor PDGFRα(+) cells. SK channel blockers and an inhibitor of phospholipase C completely abolished currents activated by UTP. In contrast, UTP activated nonselective cation currents in smooth muscle cells. Under current-clamp (current = 0), UTP induced significant hyperpolarization of PDGFRα(+) cells. MRS2500, a selective P2Y1 antagonist, did not affect UTP-activated outward currents in PDGFRα(+) cells from wild-type mice, and activation of outward currents by UTP was retained in P2ry1(-/-)/eGFP mice. As a negative control, we tested the effect of MRS2693, a selective P2Y6 agonist. This compound did not activate outward currents in PDGFRα(+) cells, and currents activated by UTP were unaffected by MRS2578, a selective P2Y6 antagonist. The nonselective P2Y receptor blocker suramin inhibited UTP-activated outward currents in PDGFRα(+) cells. Our data demonstrate that P2Y2 and/or P2Y4 receptors function, in addition to P2Y1 receptors, in activating SK currents in PDGFRα(+) cells and possibly in mediating purinergic relaxation responses in detrusor muscles.

Crucial roles of nitric oxide synthases in β-adrenoceptor-mediated bladder relaxation in mice

“…These results are not consistent with the previous reports that showed the roles of BK channels in ␤-AR-mediated bladder relaxation (11,19,46). Since SK channels are expressed and involved in human bladder smooth muscle contractility (1) and associated with purinergic relaxation in the bladder (30), we consider that the channels may have important roles in bladder smooth muscle (47). However, many functions of SK channels in the bladder remain to be fully elucidated, including the role in ␤-AR-mediated relaxation.…”

Premature contractions of the bladder are suppressed by interactions between TRPV4 and SK3 channels in murine detrusor PDGFRα+ cells

“…PDGFRα + cells have also been identified in human and guinea pig detrusor muscles 4 . These cells are closely associated with varicose nerve processes in detrusor muscles ( muscularis propria ) suggesting that PDGFRα + cells may be innervated and participate in purinergic regulation of bladder contraction 5 – 7 .…”

Should we be revisiting LUT basic science and clinical measurement of LUT sensation to improve patient care? ICI‐RS 2019

“…It has been proposed that PDGFRα + ‐IC act as a signal amplifier or “gain” between detrusor smooth muscle and afferent nerves . Another proposal is that a P2Y receptor/SK3 ion channel hyperpolarizing mechanism in IC is transmitted to and modulates the activity of the detrusor smooth muscle . To date, there is little direct evidence supporting a functional communication between smooth muscle and PDGFRα + ‐IC and a recent publication has challenged this proposition, presenting evidence suggesting that SK3‐generated hyperpolarizations in IC are not transmitted to detrusor smooth muscle cells …”