The bizarre pharmacology of the ATP release channel pannexin1

Pannexins were originally thought to represent a second and redundant family of gap junction proteins in addition to the well characterized connexins. However, it is now evident that pannexins function as unapposed membrane channels and the major role of Panx1 is that of an ATP release channel. Despite the contrasting functional roles, connexins, innexins and pannexins share pharmacological properties. Most gap junction blockers also attenuate the function of Panx1, including carbenoxolone, mefloquine and flufenamic acid. However, in contrast to connexin based gap junction channels, Panx1 channel activity can be attenuated by several groups of drugs hitherto considered very specific for other proteins. The drugs affecting Panx1 channels include several transport inhibitors, chloride channel blockers, mitochondrial inhibitors, P2X7 receptor ligands, inflammasome inhibitors and malaria drugs. These observations indicate that Panx1 may play an extended role in a wider spectrum of physiological functions. Alternatively, Panx1 may share structural domains with other proteins, not readily revealed by sequence alignments. This article is part of the Special Issue Section entitled 'Current Pharmacology of Gap Junction Channels and Hemichannels'.