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Peristalsis is impaired in the small intestine of mice lacking the P2X₃ subunit

Xiaochun Bian *†, Jianhua Ren †, Matthew DeVries *, Birthe Schnegelsberg ‡, Debra A. Cockayne ‡, Anthony P. D. W. Ford ‡ and James J. Galligan *†

P2X receptors are ATP-gated cation channels composed of one or more of seven different subunits. P2X receptors participate in intestinal neurotransmission but the subunit composition of enteric P2X receptors is unknown. In this study, we used tissues from P2X₃ wild-type (P2X₃^+/+) mice and mice in which the P2X₃ subunit gene had been deleted (P2X₃^-/-) to investigate the role of this subunit in neurotransmission in the intestine. RT-PCR analysis of mRNA from intestinal tissues verified P2X₃ gene deletion. Intracellular electrophysiological methods were used to record synaptic and drug-induced responses from myenteric neurons in vitro. Drug-induced longitudinal muscle contractions were studied in vitro. Intraluminal pressure-induced reflex contractions (peristalsis) of ileal segments were studied in vitro using a modified Trendelenburg preparation. Gastrointestinal transit was measured as the progression in 30 min of a liquid radioactive marker administered by gavage to fasted mice. Fast excitatory postsynaptic potentials recorded from S neurons (motoneurons and interneurons) were similar in tissues from P2X₃^+/+ and P2X₃^-/- mice. S neurons from P2X₃^+/+ and P2X₃^-/- mice were depolarized by application of ATP but not ,-methylene ATP, an agonist of P2X₃ subunit-containing receptors. ATP and ,-methylene ATP induced depolarization of AH (sensory) neurons from P2X₃^+/+ mice. ATP, but not ,-methylene ATP, caused depolarization of AH neurons from P2X₃^-/- mice. Peristalsis was inhibited in ileal segments from P2X₃^-/- mice but longitudinal muscle contractions caused by nicotine and bethanechol were similar in segments from P2X₃^+/+ and P2X₃^-/- mice. Gastrointestinal transit was similar in P2X₃^+/+ and P2X₃^-/- mice. It is concluded that P2X₃ subunit-containing receptors participate in neural pathways underlying peristalsis in the mouse intestine in vitro. P2X₃ subunits are localized to AH (sensory) but not S neurons. P2X₃ receptors may contribute to detection of distention or intraluminal pressure increases and initiation of reflex contractions.

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