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Single Channel Properties of Rat Acid–sensitive Ion Channel-1, -2a, and -3 Expressed in Xenopus Oocytes

Ping Zhang and Cecilia M. Canessa

Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520

Address correspondence to Cecilia M. Canessa, 333 Cedar Street, New Haven, CT 06520-8026. Fax: (203) 785-4951; E-mail: cecilia.canessa{at}yale.edu

The mammalian nervous system expresses proton-gated ion channels known as acid-sensing ion channels (ASICs). Depending on their location and specialization some neurons express more than one type of ASIC where they may form homo- or heteromeric channels. Macroscopic characteristics of the ASIC currents have been described, but little is known at the single channel level. Here, we have examined the properties of unitary currents of homomeric rat ASIC1, ASIC2a, and ASIC3 expressed in Xenopus oocytes with the patch clamp technique. We describe and characterize properties unique to each of these channels that can be used to distinguish the various types of ASIC channels expressed in mammalian neurons. The amplitudes of the unitary currents in symmetrical Na⁺ are similar for the three types of channels (23–18 pS) and are not voltage dependent. However, ASIC1 exhibits three subconductance states, ASIC2a exhibits only one, and ASIC3 none. The kinetics of the three types of channels are different: ASIC1 and ASIC2a shift between modes of activity, each mode has different open probability and kinetics. In contrast, the kinetics of ASIC3 are uniform throughout the burst of activity. ASIC1, ASIC2a, and ASIC3 are activated by external protons with apparent pH₅₀ of 5.9, 5.0, and 5.4, respectively. Desensitization in the continual presence of protons is fast and complete in ASIC1 and ASIC3 (2.0 and 4.5 s^-1, respectively) but slow and only partial in ASIC2a (0.045 s^-1). The response to external Ca²⁺ also differs: µM concentrations of extracellular Ca²⁺ are necessary for proton gating of ASIC3 (EC₅₀ = 0.28 µM), whereas ASIC1 and ASIC2a do not require Ca²⁺. In addition, Ca²⁺ inhibits ASIC1 (K_D = 9.2 ± 2 mM) by several mechanisms: decrease in the amplitude of unitary currents, shortening of the burst of activity, and decrease in the number of activated channels. Contrary to previous reports, our results indicate that the Ca²⁺ permeability of ASIC1 is very small.

Key Words: ASIC • calcium • pH • protons • kinetics

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