P2X sub(2) knockout mice and P2X sub(2)/P2X sub(3) double knockout mice reveal a role for the P2X sub(2) receptor subunit in mediating multiple sensory effects of ATP

• Published in: The Journal of physiology 2005-09, Vol.567 (2), p.621-639
• Main Authors: Cockayne, Debra A, Dunn, Philip M, Zhong, Yu, Rong, Weifang, Hamilton, Sara G, Knight, Gillian E, Ruan, Huai-Zhen, Ma, Bei, Yip, Ping, Nunn, Philip, McMahon, Stephen B, Burnstock, Geoffrey, d, Anthony PDW
• Format: Article
• Language: English
• ISSN: 0022-3751; 1469-7793

Extracellular ATP plays a role in nociceptive signalling and sensory regulation of visceral function through ionotropic receptors variably composed of P2X sub(2) and P2X sub(3) subunits. P2X sub(2) and P2X sub(3) subunits can form homomultimeric P2X sub(2), homomultimeric P2X sub(3), or heteromultimeric P2X sub(2/3) receptors. However, the relative contribution of these receptor subtypes to afferent functions of ATP in vivo is poorly understood. Here we describe null mutant mice lacking the P2X sub(2) receptor subunit (P2X sub(2) super(-/-)) and double mutant mice lacking both P2X sub(2) and P2X sub(3) subunits (P2X sub(2)/P2X sub(3) super(Dbl-/-)), and compare these with previously characterized P2X sub(3) super(-/-) mice. In patch-clamp studies, nodose, coeliac and superior cervical ganglia (SCG) neurones from wild-type mice responded to ATP with sustained inward currents, while dorsal root ganglia (DRG) neurones gave predominantly transient currents. Sensory neurones from P2X sub(2) super(-/-) mice responded to ATP with only transient inward currents, while sympathetic neurones had barely detectable responses. Neurones from P2X sub(2)/P2X sub(3) super(Dbl-/-) mice had minimal to no response to ATP. These data indicate that P2X receptors on sensory and sympathetic ganglion neurones involve almost exclusively P2X sub(2) and P2X sub(3) subunits. P2X sub(2) super(-/-) and P2X sub(2)/P2X sub(3) super(Dbl-/-) mice had reduced pain-related behaviours in response to intraplantar injection of formalin. Significantly, P2X sub(3) super(-/-), P2X sub(2) super(-/-), and P2X sub(2)/P2X sub(3) super(Dbl-/-) mice had reduced urinary bladder reflexes and decreased pelvic afferent nerve activity in response to bladder distension. No deficits in a wide variety of CNS behavioural tests were observed in P2X sub(2) super(-/-) mice. Taken together, these data extend our findings for P2X sub(3) super(-/-) mice, and reveal an important contribution of heteromeric P2X sub(2/3) receptors to nociceptive responses and mechanosensory transduction within the urinary bladder.