The Journal of Neurophysiology Vol. 77 No. 1 January 1997, pp. 93-102
Copyright ©1997 The American Physiological Society

Modulation of K⁺ Channels by Intracellular ATP in Human Neocortical Neurons

Chun Jiang^{1, 2} and Gabriel G. Haddad¹

¹ Department of Pediatrics, Section of Respiratory Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, and ² Department of Biology, Georgia State University, Atlanta, Georgia 30322-4010

Jiang, Chun and Gabriel G. Haddad. Modulation of K⁺ channels by intracellular ATP in human neocortical neurons. J. Neurophysiol. 77: 93-102, 1997. ATP-modulated K⁺ channels play an important role in regulating membrane excitability during metabolic stress. 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 physiological concentrations of ATP and selectively permeable to K⁺ were identified. One of these currents had a unitary conductance of ~47 pS 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 ~130 µM. Channel activity also was suppressed by ADP, nonhydrolyzable ATP analogue AMP-PNP, and sulfonylurea receptor/channel blocker glibenclamide. The second K⁺ current had a unitary conductance of ~200 pS and showed a weak inward rectification. Similarly, this current was inhibited by ATP (IC₅₀ = 350 µM), AMP-PNP, and glibenclamide. Unlike the small-conductance ATP-inhibitable K⁺ channel (S-K_ATP), activation of this large-conductance K⁺ channel (L-K_ATP) required the presence of micromolar concentration of Ca²⁺ in the internal solution, but charybdotoxin did not inhibit this channel. The third K⁺ current was also Ca²⁺ dependent and had a large conductance (~280 pS). It was inhibited by external charybdotoxin, iberiotoxin, and tetraethylammonium. In contrast to the other two K_ATP channels, ATP enhanced channel open-state probability and unitary conductance, and glibenclamide at concentration of 10-20 µM 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 also were observed in experiments on rat neocortical neurons. These results therefore indicate that K_ATP channels are expressed in human neocortical neurons, and two distinct K_ATP channels (S-K_ATP and L-K_ATP) 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.

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