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The Journal of Neuroscience, September 1, 2001, 21(17):6512-6521

Cell Swelling and a Nonselective Cation Channel Regulated by Internal Ca²⁺ and ATP in Native Reactive Astrocytes from Adult Rat Brain

Mingkui Chen^{1, 2} and J. Marc Simard^{1, 2, 3}

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

Hypoxia-ischemia and ATP depletion are associated with glial swelling and blebbing, but mechanisms involved in these effects remain incompletely characterized. We examined morphological and electrophysiological responses of freshly isolated native reactive astrocytes (NRAs) after exposure to NaN₃, which depletes cellular ATP. Here we report that NaN₃ caused profound and sustained depolarization attributable to activation of a novel 35 pS Ca²⁺-activated, [ATP]_i-sensitive nonselective cation (NC_Ca-ATP) channel, found in >90% of excised membrane patches. The channel was impermeable to Cl, was nearly equally permeable to monovalent cations, with permeabilities relative to K⁺ being P_Cs⁺/P_K⁺(1.06)  P_Na⁺/P_K⁺(1.04)  P_Rb⁺/P_K⁺(1.02)  P_Li⁺/P_K⁺(0.96), and was essentially impermeable to Ca²⁺ and Mg²⁺ (P_Ca²⁺/P_K⁺  P_Mg²⁺/P_K⁺ < 0.001), with intracellular Mg²⁺ (100 µM to 1 mM) causing inward rectification. Pore radius, estimated by fitting relative permeabilities of organic cations to the Renkin equation, was 0.41 nm. This channel exhibited significantly different properties compared with previously reported NC_Ca-ATP channels, including different sensitivity to block by various adenine nucleotides (EC₅₀ of 0.79 µM for [ATP]_i, with no block by AMP or ADP), and activation by submicromolar [Ca]_i. The apparent dissociation constant for Ca²⁺ was voltage dependent (0.12, 0.31, and 1.5 µM at 40, 80, and 120 mV, respectively), with a Hill coefficient of 1.5. Channel opening by [ATP]_i depletion was accompanied by and appeared to precede blebbing of the cell membrane, suggesting participation of this channel in cation flux involved in cell swelling. We conclude that NRAs from adult rat brain express a 35 pS NC_Ca-ATP channel that may play an important role in the pathogenesis of brain swelling.

Key words: cation channel; Ca²⁺; ATP; cell swelling; astrocyte; brain injury; patch clamp

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21176512-10$05.00/0

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