MODULATION OF K+ CHANNELS BY INTRACELLULAR ATP IN HUMAN NEOCORTICAL NEURONS. Jiang, Chun and Gabriel G. Haddad. Department of Pediatrics, Section of Respiratory Medicine, Yale University School of Medicine, New Haven, CT 06520, and 2 Department of Biology, Georgia State University, Atlanta, GA 30322-4010.
APStracts 3:0216N, 1996.
ABSTRACT
ATP-modulated K+ channels play an important role in regulating membrane excitability during metabolic stress. In order to characterize such K+ channels from the human brain, single channel currents were studied in excised inside-out patches from freshly dissociated human neocortical neurons. Three currents that were sensitive to physiologic concentrations of ATP and selectively permeable to K+ were identified. One of these currents had a unitary conductance of 47pS and showed a strong inward rectification with symmetric K+ concentrations across the membrane. This K+ current was inhibited by ATP in a concentration-dependent manner with an IC50 (half-inhibition of channel activity) of 130mM. Channel activity was also suppressed by ADP, non- hydrolyzable ATP analogue AMP-PNP, and sulfonylurea receptor/channel blocker glibenclamide. The second K+ current had a unitary conductance of 200pS and showed a weak inward rectification. Similarly, this current was inhibited by ATP (IC50=350mM), AMP-PNP and glibenclamide. Unlike the small-conductance ATP- inhibitable K+ channel (S-KATP), activation of this large-conductance K+ channel (L-KATP) required the presence of micromolar concentration of Ca++ in the internal solution, but charybdotoxin did not inhibit this channel. The third K+ current was also Ca++-dependent and had a large conductance (280pS). It was inhibited by external charybdotoxin, iberiotoxin and TEA. In contrast to the other two KATP channels, ATP enhanced channel open-state probability and unitary conductance, and glibenclamide at concentration of 10-20mM had no inhibitory effect on this current. K+ channels that have single-channel and pharmacological properties similar to these three human ATP-modulated K+ channels were also observed in experiments on rat neocortical neurons. These results therefore indicate that KATP channels are expressed in human neocortical neurons, and two distinct KATP channels (S-KATP and L-KATP) exist in the human and rat neurons. The observation that ATP at different concentrations modulates different K+ channels suggests that metabolic rate may be continuously sensed in neurons with resulting alterations in neuronal membrane excitability.

Received 29 January 1996; accepted in final form 4 September 1996.
APS Manuscript Number J61-6.
Article publication pending J. Neurophysiol.
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 5 November 1996