Phentolamine block of KATP channels is mediated by Kir6.2

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 94; no. 21; pp. 11716 - 11720
• Main Authors: Proks, P, Ashcroft, F M
• Format: Journal Article
• Language: English
• Published: United States National Acad Sciences 14.10.1997; National Academy of Sciences; The National Academy of Sciences of the USA
• Subjects: Anatomy & physiology; Animals; ATP-Binding Cassette Transporters; Biological Sciences; Cell Line; Female; Heart; Humans; Imidazoles - pharmacology; Ions; KATP Channels; Membrane Potentials - drug effects; Mice; Oocytes - drug effects; Oocytes - physiology; Phentolamine - pharmacology; Potassium; Potassium Channel Blockers; Potassium Channels - biosynthesis; Potassium Channels - physiology; Potassium Channels, Inwardly Rectifying; Proteins; Recombinant Proteins - antagonists & inhibitors; Recombinant Proteins - biosynthesis; Sequence Deletion; Transfection; Xenopus
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.94.21.11716

The ATP-sensitive K + -channel (K ATP channel) plays a key role in insulin secretion from pancreatic β cells. It is closed both by glucose metabolism and the sulfonylurea drugs that are used in the treatment of noninsulin-dependent diabetes mellitus, thereby initiating a membrane depolarization that activates voltage-dependent Ca 2+ entry and insulin release. The β cell K ATP channel is a complex of two proteins: Kir6.2 and SUR1. The former is an ATP-sensitive K + -selective pore, whereas SUR1 is a channel regulator that endows Kir6.2 with sensitivity to sulfonylureas. A number of drugs containing an imidazoline moiety, such as phentolamine, also act as potent stimulators of insulin secretion, but their mechanism of action is unknown. We have used a truncated form of Kir6.2, which expresses independently of SUR1, to show that phentolamine does not inhibit K ATP channels by interacting with SUR1. Instead, our results argue that phentolamine may interact directly with Kir6.2 to produce a voltage-independent reduction in channel activity. The single-channel conductance is unaffected. Although the ATP molecule also contains an imidazoline group, the site at which phentolamine blocks is not identical to the ATP-inhibitory site, because phentolamine block of an ATP-insensitive mutant (K185Q) is normal. K ATP channels also are found in the heart where they are involved in the response to cardiac ischemia: they also are blocked by phentolamine. Our results suggest that this may be because Kir6.2, which is expressed in the heart, forms the pore of the cardiac K ATP channel.