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

Abstract

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 Ba(2+), 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 microM Ba(2+), 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 Ba(2+)-sensitive leak K+ current expressed in the presumed BFC neurons by modulating its pH sensitivity.

Protein Kinase G Dynamically Modulates TASK1-Mediated Leak K+Currents in Cholinergic Neurons of the Basal Forebrain

“…The enhancement of the I-K leak by PKG activation was seen at pH 7.3 but not at pH 6.3 and 8.3, as if PKG changes the pH sensitivity of the I-K leak from the one similar to that of TASK1 to the other similar to that of TASK3 current (Toyoda et al, 2008). Such an enhancement of the I-K leak would result either from an enhancement of hidden TASK3 component or from an acidic shift in the pH sensitivity profile of TASK1 component of the I-K leak .…”

“…The procedure for slice preparation was the same as that in our previous studies (Kang et al, 2007;Toyoda et al, 2008). Using 12-16 d postnatal Wistar rats of both sexes (Charles River Breeders), slices of 300 m thickness were cut coronally from the most rostral portion of BF containing the nuclei of medial septum/diagonal band (MS/DB).…”

“…The pH sensitivity of TASK1 currents between pH 6.3 and 8.3 can be well represented as the scaled conductance (S-G x ) as defined in our previous study (Toyoda et al, 2008)…”

“…Therefore, the major component of the I-K leak in type II neurons is likely to be mediated by TASK1 channels, as reflected in its pH sensitivity profile that was almost the same as that of TASK1 current (Toyoda et al, 2008).…”

“…Recently, we have reported that the activation of NO-cGMP-PKG (protein kinase G) pathway upregulates the K leak current (I-K leak ), which is similar to TASK1 currents in its extracellular pH sensitivity, in the presumed cholinergic neurons of the basal forebrain (BF) (Kang et al, 2007;Toyoda et al, 2008). The enhancement of the I-K leak by PKG activation was seen at pH 7.3 but not at pH 6.3 and 8.3, as if PKG changes the pH sensitivity of the I-K leak from the one similar to that of TASK1 to the other similar to that of TASK3 current (Toyoda et al, 2008).…”