Purinergic neuromuscular transmission in the gastrointestinal tract; functional basis for future clinical and pharmacological studies

Nerve-mediated relaxation is necessary for the correct accomplishment of gastrointestinal (GI) motility. In the GI tract, NO and a purine are probably released by the same inhibitory motor neuron as inhibitory co-transmitters. The P2Y(1) receptor has been recently identified as the receptor responsible for purinergic smooth muscle hyperpolarization and relaxation in the human gut. This finding has been confirmed in P2Y(1)-deficient mice where purinergic neurotransmission is absent and transit time impaired. However, the mechanisms responsible for nerve-mediated relaxation, including the identification of the purinergic neurotransmitter(s) itself, are still debatable. Possibly different mechanisms of nerve-mediated relaxation are present in the GI tract. Functional demonstration of purinergic neuromuscular transmission has not been correlated with structural studies. Labelling of purinergic neurons is still experimental and is not performed in routine pathology studies from human samples, even when possible neuromuscular impairment is suspected. Accordingly, the contribution of purinergic neurotransmission in neuromuscular diseases affecting GI motility is not known. In this review, we have focused on the physiological mechanisms responsible for nerve-mediated purinergic relaxation providing the functional basis for possible future clinical and pharmacological studies on GI motility targeting purine receptors.