ATP inhibits Ins(1,4,5)P-3-evoked Ca2+ release in smooth muscle via P2Y(1) receptors

作者：MacMillan D^*; Kennedy C; McCarron J G

来源：Journal of Cell Science, 2012, 125(21): 5151-5158.

DOI：10.1242/jcs.108498

• ATP
• Smooth muscle
• Ins(1,4,5)P-3
• Calcium

Adenosine 5%26apos;-triphosphate (ATP) mediates a variety of biological functions following nerve-evoked release, via activation of either G-protein-coupled P2Y- or ligand-gated P2X receptors. In smooth muscle, ATP, acting via P2Y receptors (P2YR), may act as an inhibitory neurotransmitter. The underlying mechanism(s) remain unclear, but have been proposed to involve the production of inositol 1,4,5-trisphosphate [Ins(1,4,5)P-3] by phospholipase C (PLC), to evoke Ca2+ release from the internal store and stimulation of Ca2+-activated potassium (K-Ca) channels to cause membrane hyperpolarization. This mechanism requires Ca2+ release from the store. However, in the present study, ATP evoked transient Ca2+ increases in only similar to 10% of voltage-clamped single smooth muscle cells. These results do not support activation of KCa as the major mechanism underlying inhibition of smooth muscle activity. Interestingly, ATP inhibited Ins(1,4,5)P-3-evoked Ca2+ release in cells that did not show a Ca2+ rise in response to purinergic activation. The reduction in Ins(1,4,5)P-3-evoked Ca2+ release was not mimicked by adenosine and therefore, cannot be explained by hydrolysis of ATP to adenosine. The reduction in Ins(1,4,5)P-3-evoked Ca2+ release was, however, also observed with its primary metabolite, ADP, and blocked by the P2Y(1)R antagonist, MRS2179, and the G protein inhibitor, GDP beta S, but not by PLC inhibition. The present study demonstrates a novel inhibitory effect of P2Y1R activation on Ins(1,4,5)P-3-evoked Ca2+ release, such that purinergic stimulation acts to prevent Ins(1,4,5)P-3-mediated increases in excitability in smooth muscle and promote relaxation.

• 出版日期2012-11-1