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1 Division of Biophysics and Neurobiology, Department of Molecular Physiology, National Institute for Physiological Sciences, Okazaki, Aichi, 444-8585, Japan
2 COE Program for Brain Integration and its Disorders, Tokyo Medical and Dental University, Graduate School and Faculty of Medicine, Bunkyo, Tokyo, 113-8519, Japan
3 Solution Oriented Research for Science and Technology, Japan Science and Technology Corporation, Kawaguchi, Saitama 332-0012, Japan
It is well established that stimulation of Gq-coupled receptors such as the M1 muscarinic acetylcholine receptor inhibits KCNQ/M currents. While it is generally accepted that this muscarinic inhibition is mainly caused by the breakdown of PIP2, the role of the subsequent activation of protein kinase C (PKC) is not well understood. By reconstituting M currents in Xenopus oocytes, we observed that stimulation of coexpressed M1 receptors with 10 µM oxotremorine M (oxo-M) induces a positive shift (4–30 mV, depending on which KCNQ channels are expressed) in the conductance–voltage relationship (G–V) of KCNQ channels. When we applied phorbol 12-myristate 13-acetate (PMA), a potent PKC activator, we observed a large positive shift (17.8 ± 1.6 mV) in the G–V curve for KCNQ2, while chelerythrine, a PKC inhibitor, attenuated the shift caused by the stimulation of M1 receptors. By contrast, reducing PIP2 had little effect on the G–V curve for KCNQ2 channels; although pretreating cells with 10 µM wortmannin for 30 min reduced KCNQ2 current amplitude by 80%, the G–V curve was shifted only slightly (5 mV). Apparently, the shift induced by muscarinic stimulation in Xenopus oocytes was mainly caused by PKC activation. When KCNQ2/3 channels were expressed in HEK 293T cells, the G–V curve seemed already to be shifted in a positive direction, even before activation of PKC, and PMA failed to shift the curve any further. That alkaline phosphatase in the patch pipette shifted the G–V curve in a negative direction suggests KCNQ2/3 channels are constitutively phosphorylated in HEK 293T cells.
(Received 20 July 2005;
accepted after revision 21 September 2005;
first published online 22 September 2005)
Corresponding author K. Nakajo: Division of Biophysics and Neurobiology, Department of Molecular Physiology, National Institute for Physiological Sciences, Okazaki, Aichi, 444-8585, Japan. Email: knakajo{at}nips.ac.jp
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