Purinergic mechanisms in the control of gastrointestinal motility

Abstract

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 A 1 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 P2Y 1 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.

Purinergic receptors and synaptic transmission in enteric neurons

“…This is supported by indirect evidence from the guinea pig colon that suggests ACh and ATP are not co-stored, as there is an increase in synaptic ATP release but not ACh release from inflamed tissue [65]. For more information on the role of ATP in the enteric circuitry see Chapter 2, this issue [4].…”

“…They can differ in their level of excitability and in their ability to fire action potentials repetitively [12,15,16]. In the myenteric plexus, ATP is utilized as a transmitter or co-transmitter by at least one type of descending interneuron during local reflexes [4,17]. These descending interneurons are immunoreactive for nitric oxide synthase (NOS) and vasoactive intestinal polypeptide (VIP) and have Dogiel type I dendrites.…”

“…The molecular structure of a P2X receptor is probably a trimer consisting of one or more different subunits [30]. There are seven subtypes of P2X receptor found in adult mammalian tissue, P2X [1][2][3][4][5][6][7] [27,31]. Each subunit has two membrane-spanning domains (TM1 and TM2) and a large extracellular domain [26].…”

“…A recent study utilized a high-density oligonucleotide microarray analysis to study TNBS-induced colitis [113]. It was found that receptors for P2X 1,4,7 and P2Y 2,6 and all adenosine receptors were upregulated while there was a down regulation of P2X 2 and P2Y 1,4 receptors. Activation of A 3 receptors reversed many, but not all, of the changes in gene expression due to inflammation [113].…”

“…We will also look at the molecular properties of the native receptors, their signaling mechanisms and their role in gastrointestinal pathology. The reader is directed to other chapters in this issue for more detailed information on the role purinergic transmission plays in reflexes, and on the role of adenosine in secretion [4,5].…”