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The Journal of Neuroscience, March 1, 2000, 20(5):1710-1721

Reconstitution of Muscarinic Modulation of the KCNQ2/KCNQ3 K⁺ Channels That Underlie the Neuronal M Current

Mark S. Shapiro¹, John P. Roche¹, Edward J. Kaftan¹, Humberto Cruzblanca¹, Ken Mackie², and Bertil Hille¹

Departments of ¹ Physiology and Biophysics and ² Anesthesiology, University of Washington School of Medicine, Seattle, Washington 98195

Channels from KCNQ2 and KCNQ3 genes have been suggested to underlie the neuronal M-type K⁺ current. The M current is modulated by muscarinic agonists via G-proteins and an unidentified diffusible cytoplasmic messenger. Using whole-cell clamp, we studied tsA-201 cells in which cloned KCNQ2/KCNQ3 channels were coexpressed with M₁ muscarinic receptors. Heteromeric KCNQ2/KCNQ3 currents were modulated by the muscarinic agonist oxotremorine-M (oxo-M) in a manner having all of the characteristics of modulation of native M current in sympathetic neurons. Oxo-M also produced obvious intracellular Ca²⁺ transients, observed by using indo-1 fluorescence. However, modulation of the current remained strong even when Ca²⁺ signals were abolished by the combined use of strong intracellular Ca²⁺ buffers, an inhibitor of IP₃ receptors, and thapsigargin to deplete Ca²⁺ stores. Muscarinic modulation was not blocked by staurosporine, a broad-spectrum protein kinase inhibitor, arguing against involvement of protein kinases. The modulation was not associated with a shift in the voltage dependence of channel activation. Homomeric KCNQ2 and KCNQ3 channels also expressed well and were modulated individually by oxo-M, suggesting that the motifs for modulation are present on both channel subtypes. Homomeric KCNQ2 and KCNQ3 currents were blocked, respectively, at very low and at high concentrations of tetraethylammonium ion. Finally, when KCNQ2 subunits were overexpressed by intranuclear DNA injection in sympathetic neurons, total M current was fully modulated by the endogenous neuronal muscarinic signaling mechanism. Our data further rule out Ca²⁺ as the diffusible messenger. The reconstitution of muscarinic modulation of the M current that uses cloned components should facilitate the elucidation of the muscarinic signaling mechanism.

Key words: K⁺ channel; muscarinic receptor; G-protein; calcium; patch clamp; M current

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Copyright © 2000 Society for Neuroscience  0270-6474/00/2051710-12$05.00/0

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