Purinergic receptors and synaptic transmission in enteric neurons

Purines such as ATP and adenosine participate in synaptic transmission in the enteric nervous system as neurotransmitters or neuromodulators. Purinergic receptors are localized on the cell bodies or nerve terminals of different functional classes of enteric neurons and, with other receptors, form unique receptor complements. Activation of purinergic receptors can regulate neuronal activity by depolarization, by regulating intracellular calcium, or by modulating second messenger pathways. Purinergic signaling between enteric neurons plays an important role in regulating specific enteric reflexes and overall gastrointestinal function. In the present article, we review evidence for purine receptors in the enteric nervous system, including P1 (adenosine) receptors and P2 (ATP) receptors. We will explore the role they play in mediating fast and slow synaptic transmission and in presynaptic inhibition of transmission. Finally, we will examine the molecular properties of the native receptors, their signaling mechanisms, and their role in gastrointestinal pathology

Purinergic mechanisms in the control of gastrointestinal motility

For many years, ATP and adenosine have been implicated in movement regulation of the gastrointestinal tract. They act through three major receptor subtypes: adenosine or P1 receptors, P2X receptors and P2Y receptors. Each of these major receptor types can be subdivided into several different classes and is widely distributed amongst various neurons, muscle types, glia and interstitial cells that regulate intestinal functions. Several key roles for the different receptors and their endogenous ligands have been identified in physiological and pharmacological studies. For example, adenosine acting at A1 receptors appears to inhibit intestinal motility in various pathological conditions. Similarly, ATP acting at P2Y receptors is an important component of inhibitory neuromuscular transmission, acting as a cotransmitter with nitric oxide. ATP acting at P2X and P2Y1 receptors is important for synaptic transmission in simple descending excitatory and inhibitory reflex pathways. Some P2Y receptor subtypes prefer uridine nucleotides over purine nucleotides. Thus, roles for UTP and UDP as enteric transmitters in place of ATP cannot be excluded. ATP also appears to be important for sensory transduction, especially in chemosensitive pathways that initiate local inhibitory reflexes. Despite this evidence, data are lacking about the roles of either adenosine or ATP in more complex motility patterns such as segmentation or the interdigestive migrating motor complex. Clarification of roles for purinergic transmission in these common, but understudied, motility patterns will depend on the use of subtype-specific antagonists that in some cases have not yet been developed

Pharmacological characterization of uracil nucleotide-preferring P2Y receptors modulating intestinal motility: a study on mouse ileum

We investigated the possible modulation of the intestinal contractility by uracil nucleotides (UTP and UDP), using as model the murine small intestine. Contractile activity of a mouse ileum longitudinal muscle was examined in vitro as changes in isometric tension. Transcripts encoding for uracil-sensitive receptors was investigated by RT-PCR. UDP induced muscular contractions, sensitive to PPADS, suramin, or MRS 2578, P2Y6 receptor antagonist, and mimicked by PSB 0474, P2Y6-receptor agonist. UTP induced biphasic effects characterized by an early inhibition of the spontaneous contractile activity followed by muscular contraction. UTP excitatory effects were antagonized by PPADS, suramin, but not by MRS 2578, whilst the inhibitory effects were antagonized by PPADS but not by suramin or MRS 2578. UTPγS, P2Y2/4 receptor agonist but not 2-thio-UTP, P2Y2 receptor agonist, mimicked UTP effects. The inhibitory effects induced by UTP was abolished by ATP desensitization and increased by extracellular acidification. UDP or UTP responses were insensitive to TTX, atropine, or L-NAME antagonized by U-73122, inhibitor of phospholipase C (PLC) and preserved in the presence of nifedipine or low Ca2+ solution. Transcripts encoding the uracil nucleotide-preferring receptors were expressed in mouse ileum. Functional postjunctional uracil-sensitive receptors are present in the longitudinal muscle of the mouse ileum. Activation of P2Y6 receptors induces muscular contraction, whilst activation of P2Y4 receptors leads to inhibition of the contractile activity. Indeed, the presence of atypical UTP-sensitive receptors leading to muscular contraction is suggested. All uracil-sensitive receptors are linked to the PLC pathway