Dual regulation of the ATP-sensitive potassium channel by caffeine.
نویسندگان
چکیده
ATP-sensitive potassium (K(ATP)) channels couple cellular metabolic status to changes in membrane electrical properties. Caffeine (1,2,7-trimethylxanthine) has been shown to inhibit several ion channels; however, how caffeine regulates K(ATP) channels was not well understood. By performing single-channel recordings in the cell-attached configuration, we found that bath application of caffeine significantly enhanced the currents of Kir6.2/SUR1 channels, a neuronal/pancreatic K(ATP) channel isoform, expressed in transfected human embryonic kidney (HEK)293 cells in a concentration-dependent manner. Application of nonselective and selective phosphodiesterase (PDE) inhibitors led to significant enhancement of Kir6.2/SUR1 channel currents. Moreover, the stimulatory action of caffeine was significantly attenuated by KT5823, a specific PKG inhibitor, and, to a weaker extent, by BAPTA/AM, a membrane-permeable Ca(2+) chelator, but not by H-89, a selective PKA inhibitor. Furthermore, the stimulatory effect was completely abrogated when KT5823 and BAPTA/AM were co-applied with caffeine. In contrast, the activity of Kir6.2/SUR1 channels was decreased rather than increased by caffeine in cell-free inside-out patches, while tetrameric Kir6.2LRKR368/369/370/371AAAA channels were suppressed regardless of patch configurations. Caffeine also enhanced the single-channel currents of recombinant Kir6.2/SUR2B channels, a nonvascular smooth muscle K(ATP) channel isoform, although the increase was smaller. Moreover, bidirectional effects of caffeine were reproduced on the K(ATP) channel present in the Cambridge rat insulinoma G1 (CRI-G1) cell line. Taken together, our data suggest that caffeine exerts dual regulation on the function of K(ATP) channels: an inhibitory regulation that acts directly on Kir6.2 or some closely associated regulatory protein(s), and a sulfonylurea receptor (SUR)-dependent stimulatory regulation that requires cGMP-PKG and intracellular Ca(2+)-dependent signaling.
منابع مشابه
Synthesis and Vasorelaxant Effect of 9-aryl-1,8-acridinediones as Potassium Channel Openers in Isolated Rat Aorta
ATP-sensitive potassium (KATP) channel openers have a relaxation effect due to the lower cellular membrane potential and inhibit calcium influx. There has been considerable interest in exploring KATP channel openers in the treatment of various diseases such as cardiovascular, cerebrovascular, and urinary system disease and premature labor. The purpose of this study was to synthesize 3,3,6,6-tet...
متن کاملSynthesis and Vasorelaxant Effect of 9-aryl-1,8-acridinediones as Potassium Channel Openers in Isolated Rat Aorta
ATP-sensitive potassium (KATP) channel openers have a relaxation effect due to the lower cellular membrane potential and inhibit calcium influx. There has been considerable interest in exploring KATP channel openers in the treatment of various diseases such as cardiovascular, cerebrovascular, and urinary system disease and premature labor. The purpose of this study was to synthesize 3,3,6,6-tet...
متن کاملRole of Nitric Oxide and ATP-Sensitive K+ Channels in Regulation of Basal Blood Flow and Hypercapnic Vasodilatation of Cerebral Blood Vessels in Rabbit
Background: The mechanisms underlying cerebral hypercapnic vasodilatation are not fully understood. Objective: To investigate the role of nitric oxide (NO) and ATP-sensitive potassium (KATP) channels in basal blood flow regulation and hypercapnia-induced vasodilatation in rabbit cerebral blood vessels. Methods: The change in cerebral blood flow was measured by a laser Doppler flowmeter in 18 Ne...
متن کاملEvidences on the existence of a new potassium channel in the rough endoplasmic reticulum (RER) of rat hepatocytes
Introduction: we have recently reported the presence of two potassium currents with 598 and 368 pS conductance in the rough endoplasmic reticulum (RER) membrane. The 598 pS channel was voltage dependent and ATP sensitive. However, the 368 pS channel was rarely observed and its identity remained obscure. Since cationic channels in intracellular organelles such as mitochondria and RER play imp...
متن کاملBiophysical and electropharmacological properties of single mitoKATP channel in rat brain mitochondrial inner membrane
Introduction: Different ATP-sensitive potassium channels have been detected in the mitochondrial inner membrane of cells. They are suggested to be involved in cell processes including cell protection. Here, we characterized the biophysical and electropharmacological properties of a KATP channel in the brain mitochondrial inner membranes. Methods: After removing and homogenizing the rat brain...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- American journal of physiology. Cell physiology
دوره 292 6 شماره
صفحات -
تاریخ انتشار 2007