Abstract
High frequency firing in mammalian neurons requires ultra-rapid delayed rectifier potassium currents generated by homomeric or heteromeric assemblies of Kv3.1 and Kv3.2 potassium channel alpha subunits. Kv3.1 alpha subunits can also form slower activating channels by coassembling with MinK-related peptide 2 (MiRP2), a single transmembrane domain potassium channel ancillary subunit. Here, using channel subunits cloned from rat and expressed in Chinese hamster ovary cells, we show that modulation by MinK, MiRP1, and MiRP2 is a general mechanism for slowing of Kv3.1 and Kv3.2 channel activation and deactivation and acceleration of inactivation, creating a functionally diverse range of channel complexes. MiRP1 also negatively shifts the voltage dependence of Kv3.1 and Kv3.2 channel activation. Furthermore, MinK, MiRP1, and MiRP2 each form channels with Kv3.1-Kv3.2 heteromers that are kinetically distinct from one another and from MiRP/homomeric Kv3 channels. The findings illustrate a mechanism for dynamic expansion of the functional repertoire of Kv3.1 and Kv3.2 potassium currents and suggest roles for these alpha subunits outside the scope of sustained rapid neuronal firing.
Highlights
The distinct electrical properties of different subtypes of neurons are determined by the biophysical characteristics of the intrinsic voltage-dependent conductances that they express
Using channel subunits cloned from rat and expressed in Chinese hamster ovary cells, we show that modulation by MinK, MiRP1, and MinK-related peptide 2 (MiRP2) is a general mechanism for slowing of Kv3.1 and Kv3.2 channel activation and deactivation and acceleration of inactivation, creating a functionally diverse range of channel complexes
Co-immunoprecipitations were performed to assess whether Kv3.1 or Kv3.2 ␣ subunits form stable complexes with MinK and MiRP1 when expressed in Chinese Hamster Ovary (CHO) cells
Summary
Voltage-gated potassium channel; MiRP, MinK-related peptide; CHO, Chinese hamster ovary; HA, hemagglutinin; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid. Rapid activation and deactivation kinetics and an especially depolarized activation voltage, activating only when the membrane potential is more positive than Ϫ10 mV [3] These biophysical properties, combined with the expression patterns of Kv3 ␣ subunits in mammalian brain, support a central role for Kv3 channels in determining the ability of neurons to follow high frequency input and sustain rapid firing [3,4,5,6,7,8,9]. Kv3.1 and Kv3.2 are highly enriched in neurons that fire at high frequencies, such as fast spiking interneurons of the cortex and hippocampus [9, 12], and neurons in the globus pallidus [7, 13] Their unusually rapid activation and deactivation rates allow channels containing Kv3.1 and Kv3.2 ␣ subunits to repolarize action potentials quickly without compromising the threshold for action potential generation by promoting a rapid afterhyperpolarization period, minimizing the rate of recovery of sodium channel inactivation. The data raise the possibility that MiRP-Kv3 channels may underlie a variety of voltage-gated currents in non-rapid firing cells in brain and other tissues
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