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The Journal of Neuroscience, September 17, 2003, 23(24):8568-8577

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Functional Coupling between Sulfonylurea Receptor Type 1 and a Nonselective Cation Channel in Reactive Astrocytes from Adult Rat Brain

Mingkui Chen,¹ Yafeng Dong,² and J. Marc Simard^1,2,3

Departments of ¹Neurosurgery, ²Pathology, and ³Physiology, University of Maryland at Baltimore, Baltimore, Maryland 21201

We previously identified a novel, nonselective cation channel in native reactive (type R1) astrocytes (NR1As) from injured rat brain that is regulated by cytoplasmic Ca²⁺ and ATP (NC_Ca-ATP) and exhibits sensitivity to block by adenine nucleotides similar to that of sulfonylurea receptor type 1 (SUR1). Here we show that SUR1 is involved in regulation of this channel. NR1As within the site of injury and after isolation exhibited specific binding of FITC-tagged glibenclamide and were immunolabeled with anti-SUR1 antibody, but not with anti-SUR2, anti-Kir6.1 or anti-Kir6.2 antibodies, indicating absence of ATP-sensitive K⁺ (K_ATP) channels. RT-PCR confirmed transcription of mRNA for SUR1 but not SUR2. Several properties previously associated exclusively with SUR1-regulated K_ATP channels were observed in patch-clamp experiments using Cs⁺ as the charge carrier: (1) the sulfonylureas, glibenclamide and tolbutamide, inhibited NC_Ca-ATP channels with EC₅₀ values of 48 nM and 16.1 µM, respectively; (2) inhibition by sulfonylureas was lost after exposure of the intracellular face to trypsin or anti-SUR1 antibody; (3) channel inhibition was caused by a change in kinetics of channel closing, with no change in channel amplitude or open-channel dwell times; and (4) the SUR activator ("K_ATP channel opener"), diazoxide, activated the NC_Ca-ATP channel, whereas pinacidil and cromakalin did not. Also, glibenclamide prevented cell blebbing after ATP depletion, whereas blebbing was produced by exposure to diazoxide. Our data indicate that SUR1 is functionally coupled to the pore-forming portion of the NC_Ca-ATP channel, providing the first demonstration of promiscuity of SUR1 outside of the K⁺ inward rectifier family of channels.

Key words: sulfonylurea; SUR1; glibenclamide; diazoxide; cation channel; cell swelling; astrocyte; brain injury; patch clamp

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Received July 1, 2003; revised July 1, 2003; accepted July 21, 2003.

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