Molecular Cloning and Functional Expression of KCNQ5, a Potassium Channel Subunit That May Contribute to Neuronal M-current Diversity

Abstract

We have isolated KCNQ5, a novel human member of the KCNQ potassium channel gene family that is differentially expressed in subregions of the brain and in skeletal muscle. When expressed in Xenopus oocytes, KCNQ5 generated voltage-dependent, slowly activating K ؉ -selective currents that displayed a marked inward rectification at positive membrane voltages. KCNQ5 currents were insensitive to the K ؉ channel blocker tetraethylammonium but were strongly inhibited by the selective M-current blocker linopirdine. Upon coexpression with the structurally related KCNQ3 channel subunit, current amplitudes increased 4 -5-fold. Compared with homomeric KCNQ5 currents, KCNQ3/KCNQ5 currents also displayed slower activation kinetics and less inward rectification, indicating that KCNQ5 combined with KCNQ3 to form functional heteromeric channel proteins. This functional interaction between KCNQ5 and KCNQ3, a component of the M-channel, suggests that KCNQ5 may contribute to a diversity of heteromeric channels underlying native neuronal M-currents.

Effects of KCNQ channel modulators on the M-type potassium current in primate retinal pigment epithelium

“…Linopirdine and its more potent analog XE991 have been useful in the study of heterologously ex- M. Although linopirdine and XE991 also block other voltagedependent currents (5,26,38), they do so at higher concentrations (IC 50 Ͼ100 M). We found that the M-type current in RPE cells was quite sensitive to block by linopirdine, with an apparent IC 50 of 0.5 M. Consistent with our previous finding (41), XE991 was also effective, with an apparent IC 50 of 0.3 M. The IC 50 values for the block of the M-type current by linopirdine and XE991 are similar to those of KCNQ1, with IC 50 for block of 9 and 0.8 M, respectively (35), but are about an order of magnitude lower than those of homomeric KCNQ4 and KCNQ5 channels, with IC 50 of 6 -14 and 16 -75 M, respectively (18,27,30). This would seem to argue against the involvement of KCNQ4 or KCNQ5 channels in the M-type current and in favor of KCNQ1, but it is possible that the M-type channel sensitivity to these blockers is influenced by interactions with KCNE subunits or other factors.…”

Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy

“…Figure 2 shows that heterologous expression of homomeric WT Kv7.5 channels yielded voltage-dependent K þ currents that activated slowly upon depolarization with a V 1/2 of activation of À46.2 5 1.8 mV (n ¼ 7), as has been described previously. 8,21 All four aberrant proteins exhibited robust functional expression when expressed as homomers. Compared with WT channels, each altered channel modified gating properties (Figures 2 and 3), and this was evident in the activation (Figure 2A) and deactivation ( Figure 3A) current traces.…”

“…Kv7.5 subunits might also co-assemble with Kv7.3 subunits in vivo to contribute to the M-current, 8,21 as well as KCNE1 and KCNE3 (MIM: 604433), which are endogenously expressed in Xenopus oocytes, and we have not explored the effect of the de novo mutations in such protein complexes.…”

Ion channel regulation by β-secretase BACE1 – enzymatic and non-enzymatic effects beyond Alzheimer's disease

“…[79][80][81] KCNQ5 has further been identified as a neuronal KCNQ member. [82][83][84] A complex molecular network is regulating the expression, localization, and gating of KCNQ channels.…”