Bidirectional control of BK channel open probability by CAMKII and PKC in medial vestibular nucleus neurons

Abstract

van Welie I, du Lac S. Bidirectional control of BK channel open probability by CAMKII and PKC in medial vestibular nucleus neurons. J Neurophysiol 105: 1651-1659, 2011. First published February 9, 2011 doi:10.1152/jn.00058.2011.-Large conductance K ϩ (BK) channels are a key determinant of neuronal excitability. Medial vestibular nucleus (MVN) neurons regulate eye movements to ensure image stabilization during head movement, and changes in their intrinsic excitability may play a critical role in plasticity of the vestibulo-ocular reflex. Plasticity of intrinsic excitability in MVN neurons is mediated by kinases, and BK channels influence excitability, but whether endogenous BK channels are directly modulated by kinases is unknown. Double somatic patch-clamp recordings from MVN neurons revealed large conductance potassium channel openings during spontaneous action potential firing. These channels displayed Ca 2ϩ and voltage dependence in excised patches, identifying them as BK channels. Recording isolated single channel currents at physiological temperature revealed a novel kinase-mediated bidirectional control in the range of voltages over which BK channels are activated. Application of activated Ca 2ϩ /calmodulin-dependent kinase II (CAMKII) increased BK channel open probability by shifting the voltage activation range towards more hyperpolarized potentials. An opposite shift in BK channel open probability was revealed by inhibition of phosphatases and was occluded by blockade of protein kinase C (PKC), suggesting that active PKC associated with BK channel complexes in patches was responsible for this effect. Accordingly, direct activation of endogenous PKC by PMA induced a decrease in BK open probability. BK channel activity affects excitability in MVN neurons and bidirectional control of BK channels by CAMKII, and PKC suggests that cellular signaling cascades engaged during plasticity may dynamically control excitability by regulating BK channel open probability. phosphorylation; firing rate potentiation; vestibulo-ocular reflex; vestibular nucleus; calmodulin-dependent kinase II; protein kinase C; large conductance potassium channels PLASTICITY IN NEURONAL SPIKE output can occur via changes in synaptic strength but also via modulation of intrinsic excitability [for reviews, see Daoudal and Debanne (2003)

Modeling interactions between voltage-gated Ca2+channels and KCa1.1 channels

“…2A, right, dark blue). Cav2.2 channels have a much higher single channel conductance, maximal P o , and inactivate slowly 5 , 6 , 10 , 12 . A single Cav2.2 channel at 20 nm distance from a KCa1.1 channel was thus able to increase the KCa1.1 P o to 0.14, or twice that of a single Cav3.2 channel (Fig.…”

Decreased Tonic Inhibition in Cerebellar Granule Cells Causes Motor Dysfunction in a Mouse Model of Angelman Syndrome

“…The spike rate adaptation with lower amplitude after hyperpolarization of cerebellar granule cells might result from deactivation of large-conductance K + (BK) channels (48) due to the decreased activity of calcium/calmodulin-dependent protein kinase II in Ube3a m−/p+ mice (5). Previous in vivo analysis in Ube3a m−/p+ mice showed that aberrant Purkinje cell firing consisted of the increased frequency and rhythmicity of simple spikes (49).…”

BK Channels Are Required for Multisensory Plasticity in the Oculomotor System

“…It is possible, however, that UVD affects excitability via signaling pathways distinct from those critical for firing rate potentiation. The downstream consequence of the reduced [Ca2+] and CaMKII levels that trigger FRP is a marked reduction of BK currents (Nelson et al, 2005; van Welie and du Lac 2011). To determine whether BK channels are affected by UVD, we assessed the actions of the specific BK channel antagonist iberiotoxin (IBTX) on MVN neuronal excitability, as described previously (Nelson et al, 2005).…”

“…SK-type calcium activated potassium conductances exert a predominant influence on excitability gain in MVN neurons (Smith et al, 2002) but do not play a role in firing rate potentiation (Nelson et al, 2003). Peripheral vestibular dysfunction additionally induces dynamic changes in glucocorticoids (Cameron and Dutia, 1999), nitric oxide (Anderson, et al, 1998; Park and Jeong, 2000), and neurotransmitter levels (Yamanaka et al, 2000; Vibert et al, 2000; Johnston et al, 2001; Bergquist et al, 2008) which may enhance or counteract the effects of firing rate potentiation on MVN neuronal excitability, possibly via alterations in sodium channel gating, subthreshold potassium currents, or enzymatic regulation of BK channels (Shao et al, 2009; van Welie and du Lac, 2011). Heterogeneity of physiological factors that modulate spontaneous firing rate and gain differentially across MVN cell types (Shin et al, 2011) could account for differences in our study between the time courses and magnitudes of plasticity in measures of excitability and behavior.…”

“…Interestingly, reductions in calcium-dependent potassium currents are commonly associated with behaviorally-induced excitability increases (Alkon et al, 1985; Bekisz et al, 2010; Matthews et al, 2008). Bidirectional modulation of BK currents by kinases and phosphatases (Reinhart et al, 1991; van Welie and du Lac, 2011) serves as a potential substrate for their activity-dependent regulation. Although BK channels are expressed ubiquitously in neurons throughout the sensory-motor circuits which signal via modulations in firing rate, they are dispensable for both linear rate coding and for burst firing, making them well suited to serve as a dynamically modifiable gain-control knob (Nelson et al, 2003).…”