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CELLULAR AND MOLECULAR

Involvement of P2Y₁ and P2Y₁₁ Purinoceptors in Parasympathetic Inhibition of Colonic Smooth Muscle

Departments of Physiology (B.F.K.) and Biochemistry and Molecular Biology (A.T.-N.), University College London, London, United Kingdom

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 P2Y₁ and P2Y₁₁ receptors, and where transcripts for both genes have been found. A partial sequence for P2Y₁₁ protein was identified; the full-length P2Y₁ sequence has already been described. P2Y₁ and P2Y₁₁ proteins were localized by immunohistochemistry in smooth muscle cells. P2X₂ and P2X₃ proteins were also localized in motoneurons of the myenteric plexus. β-Methylene-ATP (βmeATP) and dibenzoyl-ATP (BzATP) evoked fast relaxations in the taenia, and they were inhibited by the P2Y₁ receptor antagonist 2'-deoxy-N⁶-methyladenosine 3',5'-bisphosphate (MRS2179). However, βmeATP and BzATP may stimulate neuronal P2X receptors to release ATP, which then acts on P2Y₁ receptors. In accordance, fast relaxations evoked by βmeATP and BzATP were inhibited by the P2X₃ 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 P2Y₁, P2X₃, and P2X_2/3 receptors were blocked and adenosine was removed enzymatically, βmeATP 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. βmeATP and BzATP were confirmed as agonists, and Reactive Red as an antagonist, of human P2Y₁₁ receptors. In summary, G_q-coupled P2Y₁ receptors are involved mainly in fast relaxations, whereas G_qand G_s-coupled P2Y₁₁ 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).

Address correspondence to: Dr. Brian F. King, Department of Physiology (Hampstead Campus), Medical School, University College London, Rowland Hill St., London, NW3 2PF, UK. E-mail: b.king{at}medsch.ucl.ac.uk