Involvement of P2Y1 and P2Y11 purinoceptors in parasympathetic inhibition of colonic smooth muscle.

Purinergic signaling was first recognized in the guinea pig (Cavia porcellus) taenia coli, where relaxation of smooth muscle by nerve-released ATP may involve the activation of P2Y(1) and P2Y(11) receptors, and where transcripts for both genes have been found. A partial sequence for P2Y(11) protein was identified; the full-length P2Y(1) sequence has already been described. P2Y(1) and P2Y(11) proteins were localized by immunohistochemistry in smooth muscle cells. P2X(2) and P2X(3) proteins were also localized in motoneurons of the myenteric plexus. alphabeta-Methylene-ATP (alphabetameATP) and dibenzoyl-ATP (BzATP) evoked fast relaxations in the taenia, and they were inhibited by the P2Y(1) receptor antagonist 2'-deoxy-N(6)-methyladenosine 3',5'-bisphosphate (MRS2179). However, alphabetameATP and BzATP may stimulate neuronal P2X receptors to release ATP, which then acts on P2Y(1) receptors. In accordance, fast relaxations evoked by alphabetameATP and BzATP were inhibited by the P2X(3) and P2X(2/3) receptor antagonist 5-({[3-phenoxybenzyl][(1S)-1,2,3,4-tetrahydro-1-naphthalenyl] amino} carbonyl)-1,2,4-benzene-tricarboxylic acid (A317491). When P2Y(1), P2X(3), and P2X(2/3) receptors were blocked and adenosine was removed enzymatically, alphabetameATP and BzATP evoked slow relaxations that were inhibited by Reactive Red. Fast and slow relaxations involve small and large conductance calcium-activated potassium channels; the latter are dependent on intracellular cyclic AMP levels, which altered the duration and amplitude of relaxations. alphabetameATP and BzATP were confirmed as agonists, and Reactive Red as an antagonist, of human P2Y(11) receptors. In summary, G(q)-coupled P2Y(1) receptors are involved mainly in fast relaxations, whereas G(q)and G(s)-coupled P2Y(11) receptors are involved in both fast and slow relaxations. These P2Y receptor subtypes, plus neuronal P2X receptors, may explain the phenomenon of parasympathetic inhibition first described by Langley (1898).