Neurotransmitter Modulation of Small-Conductance Ca²⁺-Activated K⁺ Channels by Regulation of Ca²⁺ Gating

Small-conductance Ca²⁺-activated K⁺ (SK) channels are widely expressed in neuronal tissues where they underlie postspike hyperpolarizations, regulate spike-frequency adaptation, and shape synaptic responses. SK channels constitutively interact with calmodulin (CaM), which serves as Ca²⁺ sensor, and with protein kinase CK2 and protein phosphatase 2A, which modulate their Ca²⁺ gating. By recording coupled activities of Ca²⁺ and SK2 channels, we showed that SK2 channels can be inhibited by neurotransmitters independently of changes in the activity of the priming Ca²⁺ channels. This inhibition involves SK2-associated CK2 and results from a 3-fold reduction in the Ca²⁺ sensitivity of channel gating. CK2 phosphorylated SK2-bound CaM but not KCNQ2-bound CaM, thereby selectively regulating SK2 channels. We extended these observations to sensory neurons by showing that noradrenaline inhibits SK current and increases neuronal excitability in a CK2-dependent fashion. Hence, neurotransmitter-initiated signaling cascades can dynamically regulate Ca²⁺ sensitivity of SK channels and directly influence somatic excitability.