Differential expression of KCNQ2 splice variants: Implications to M current function during neuronal development

The KCNQ family of K+ channels has been implicated in several cardiac and n eurological disease pathologies. KCNQ2 (Q2) is a brain-derived gene, which in association with KCNQ3 (Q3) has been shown to provide a molecular basis for the neuronal M current. We have cloned a long (Q2L) and a short (Q2S) s plice variant of the human KCNQ2 gene; these variants differ in their C-ter minal tail. Northern blot analysis reveals that Q2L is preferentially expre ssed in differentiated neurons, whereas the Q2S transcript is prominent in fetal brain, undifferentiated neuroblastoma cells, and brain tumors. Q2L, t ransfected into mammalian cells, produces a slowly activating, noninactivat ing voltage-gated K+ current that is blocked potently by tetraethylammonium (TEA; IC50, 0.14 mM). Q2S on the other hand produces no measurable potassi um currents. Cotransfection of Q2S with either Q2L, Q3, or Q2L/Q3 heteromul timers results in attenuation of K+ current, the suppression being most pro found for Q3. Inclusion of Q2S in the heteromultimer also positively shifts the voltage dependence of current activation and alters affinity for the T EA block, suggesting that under these conditions, some Q2S subunits incorpo rate into functional channels on the plasma membrane. In view of the crucia l role of M currents in modulating neuronal excitability, our findings prov ide important insight into the functional consequences of differential expr ession of KCNQ2 splice variants: dampened potassium conductances in the dev eloping brain could shape firing repertoires to provide cues for proliferat ion rather than differentiation.