MODULATION OF K+ CHANNELS BY INTRACELLULAR ATP IN HUMAN NEOCORTICAL
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.
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
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