P2Y1 receptors mediate inhibitory neuromuscular transmission and enteric neuronal activation in small intestine

There is increasing evidence that adenosine 5'-triphosphate or a related purine plays a crucial role in smooth muscle relaxation and enteric synaptic neurotransmission. Accordingly, the aim of the present work is to investigate the role P2Y(1) receptors in purinergic inhibitory neurotransmission (pig ileum) and enteric neuronal activation in the small intestine (guinea-pig ileum). Using contractility measurements, micro-electrode recordings and Ca(2+) imaging we found that (i) adenosine 5'-Omicron-2-thiodiphosphate (ADPbetaS) (10 micromol L(-1)) caused smooth muscle relaxation and hyperpolarization that was antagonized by MRS2179 (10 micromol L(-1)) a P2Y(1) receptor antagonist and apamin (1 micromol L(-1)); (ii) electrical field stimulation (EFS) caused a non-nitrergic inhibitory junction potential (IJP) and relaxation that was antagonized by MRS2179 (10 micromol L(-1)); (iii) P2Y(1) receptors were immunolocalized in smooth muscle cells and enteric neurons; (i.v.) superfusion of ADPbetaS (1 micromol L(-1)) induced Ca(2+) transients in myenteric neurons that were inhibited by MRS2179 (1 micromol L(-1)), but not by tetrodotoxin (1 micromol L(-1)); and (v) EFS induced calcium transients were partially inhibited by MRS2179 (1 micromol L(-1)). We conclude that in the small intestine purinergic neuromuscular transmission responsible for the IJP and non-nitrergic relaxation is mediated by P2Y(1) receptors located in smooth muscle cells. Functional P2Y(1) receptors are also present in guinea-pig myenteric neurons. Therefore, P2Y(1) receptors might be an important pharmacological target to modulate gastrointestinal functions.