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cGMP Activates a pH-Sensitive Leak K⁺ Current in the Presumed Cholinergic Neuron of Basal Forebrain

¹Department of Neuroscience and Oral Physiology, Osaka University Graduate School of Dentistry; ²Division for Interdisciplinary Dentistry, Osaka University Dental Hospital, Osaka; ³The Research Institute of Personalized Health Science and ⁴Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Hokkaido; and ⁵Department of Morphological Brain Science, Graduate School of Medicine, Kyoto University, Kyoto, Japan

Submitted 23 September 2007; accepted in final form 18 February 2008

In an earlier study, we demonstrated that nitric oxide (NO) causes the long-lasting membrane hyperpolarization in the presumed basal forebrain cholinergic (BFC) neurons by cGMP–PKG-dependent activation of leak K⁺ currents in slice preparations. In the present study, we investigated the ionic mechanisms underlying the long-lasting membrane hyperpolarization with special interest in the pH sensitivity because 8-Br-cGMP–induced K⁺ current displayed Goldman–Hodgkin–Katz rectification characteristic of TWIK-related acid-sensitive K⁺ (TASK) channels. When examined with the ramp command pulse depolarizing from –130 to –40 mV, the presumed BFC neurons displayed a pH-sensitive leak K⁺ current that was larger in response to pH decrease from 8.3 to 7.3 than in response to pH decrease from 7.3 to 6.3. This K⁺ current was similar to TASK1 current in its pH sensitivity, whereas it was highly sensitive to Ba²⁺, unlike TASK1 current. The 8-Br-cGMP–induced K⁺ currents in the presumed BFC neurons were almost completely inhibited by lowering external pH to 6.3 as well as by bath application of 100 µM Ba²⁺, consistent with the nature of the leak K⁺ current expressed in the presumed BFC neurons. After 8-Br-cGMP application, the K⁺ current obtained by pH decrease from 7.3 to 6.3 was larger than that obtained by pH decrease from pH 8.3 to 7.3, contrary to the case seen in the control condition. These observations strongly suggest that 8-Br-cGMP activates a pH- and Ba²⁺-sensitive leak K⁺ current expressed in the presumed BFC neurons by modulating its pH sensitivity.