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

Abstract

Summary Small-conductance Ca2+-activated K+ (SK) channels are widely expressed in neuronal tissues where they underlie post-spike 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 steady-state Ca2+ sensitivity of channel gating. CK2 phosphorylated SK2-bound CaM but not KCNQ2-bound CaM, thereby selectively regulating Ca2+ gating of SK2 channels. We extended these observations to sensory neurons by showing that noradrenaline inhibits SK current and enhances signaling of primary afferent neurons in a CK2- dependent fashion. Hence, neurotransmitter-initiated signaling cascades can dynamically regulate Ca2+ sensitivity of SK channels and directly influence somatic excitability.

Channel-anchored Protein Kinase CK2 and Protein Phosphatase 1 Reciprocally Regulate KCNQ2-containing M-channels via Phosphorylation of Calmodulin

“…Because TBB has been widely used in cellular experiments (14,16,17), we tested the effect of TBB on KCNQ2 current. TBB rapidly suppressed KCNQ2 current (Fig.…”

“…However, because protein kinase CK2 is constitutively active and phosphorylates a wide range of proteins (14,15), it has long been considered to be engaged in housekeeping functions (14). This traditional view has been revised by recent studies, where CK2-mediated phosphorylation of CaM was shown to play an active role in muscarinic facilitation of long term potentiation in the hippocampus by modulating SK2 channel activity (16,17).…”

Distinct Effects of Repeated Restraint Stress on Basolateral Amygdala Neuronal Membrane Properties in Resilient Adolescent and Adult Rats

“…The amygdala circuits that regulate fear and anxiety are hypothesized to be an important target of some of these genetic differences (Hariri et al, 2002;Smolka et al, 2005;Jovanovic and Ressler, 2010;Mozhui et al, 2010;Alexander et al, 2012;Hermann et al, 2012;White et al, 2012;Rogers et al, 2013;Volman et al, 2013). Many of these transmitter systems listed above directly or indirectly modulate the same signaling cascades that modify SK channel function (Pedarzani and Storm, 1995;Pedarzani et al, 1998;Lee et al, 2003;Bildl et al, 2004;Ren et al, 2006;Maingret et al, 2008), leading to changes in the excitability of amygdala neurons.…”

Dynamic excitation states and firing patterns are controlled by sodium channel kinetics in myenteric neurons: a simulation study

“…1B, bottom). The N-shaped momentary I-V having an inward current-induced limb of negative slope and 3 zero-current points is well known to be indicative of the membrane property to generate a self-maintained (regenerative) depolarization 6,7 that is necessary for the AP. Indeed, a regenerative AP recorded from simulated myenteric lasts approximately as long (about 3 ms) as the momentary I-V of the total current remains N-shaped with 3 zero current points (Fig.…”

“…[6][7][8] Information of particular importance is carried by behavior of crosspoints of these time-evolving I-Vs with the voltage axis as these points (of zero current) indicate the membrane characteristic electrical states and their stability (see e.g., Fig. 8.12 in 6 ).…”