The journey to establish purinergic signalling in the gut

Although the concept of purinergic signalling arose from experiments designed to find the identity of the non-adrenergic, non-cholinergic (NANC) inhibitory neurotransmitter in the gut, it has taken many years for the more general importance of the various roles of ATP as a physiological messenger in the gut to be recognized. Firstly, vasoactive intestitial polypeptide (VIP) and later nitric oxide (NO) were considered the NANC transmitter and it was only later, after the concept of cotransmission was established, that ATP, NO and VIP were recognized as cotransmitters in NANC nerves, although the proportions vary in different gut regions. Recently, many purinoceptor subtypes have been identified on myenteric, submucosal motor, sensory and interneurons involved in synaptic neurotransmission and neuromodulation and reflex activity of several kinds, including ascending excitatory and descending inhibitory reflex pathways. Nucleotide receptors have been shown to be expressed on enteric glial cells and interstitial cells of Cajal. Purinergic mechanosensory transduction, involving release of ATP from mucosal epithelial cells during distension to stimulate subepithelial nerve endings of intrinsic and extrinsic sensory nerves to modulate peristalsis and initiate nociception respectively, is attracting current attention. Exciting new areas of interest about purinergic signalling in the gut include: involvement of purines in development, ageing and regeneration, including the role of stem cells; studies of the involvement of nucleotides in the activity of the gut of invertebrates and lower vertebrates; and the pathophysiology of enteric purinergic signalling in diseases including irritable bowel syndrome, postoperative ileus, oesophageal reflux, constipation, diarrhoea, diabetes, Chaga's and Hirschprung's disease.