, 1998), whereas Kv2 channel gating is shifted to more positive v

, 1998), whereas Kv2 channel gating is shifted to more positive voltages by r-stromatoxin-1 (Escoubas et al., 2002). Most neuronal Kv2 channels contain Kv2.1 subunits, as in the hippocampus (Du et al., 2000), MEK inhibitor clinical trial whereas Kv2.2 has a more restricted expression, such as the medial nucleus of the trapezoid body (MNTB) (Johnston et al., 2008). Neuronal nitric oxide synthase (nNOS) is widely expressed in the brain, activated by Ca2+ influx through synaptic NMDARs (Brenman et al., 1996 and Garthwaite et al., 1988) and linked with synaptic plasticity in the cerebellum (Boxall and Garthwaite, 1996 and Shin and Linden, 2005), hippocampus (Lu et al., 1999),

and neocortex (Hardingham and Fox, 2006). Nitric oxide (NO) is associated BMN 673 with signaling across many physiological systems, including cardiovascular, immune, and enteric and central nervous systems, and related to disease and pathological states (Garthwaite, 2008 and Steinert et al., 2010a). nNOS is often localized to subpopulations of neurons in a given region, and the source or the specific targets of nitrergic signaling are hard to identify at a molecular level or in a physiological context. Soluble guanylyl cyclase (sGC) is the major NO receptor and hence, cGMP-mediated activation of PKG and subsequent

changes in the balance of kinase/phosphatase activity modulates target protein phosphorylation, such as ligand- (Serulle et al., 2007) and voltage-gated ion channels (Park et al., 2006). Recent evidence from the auditory brain stem demonstrates that Kv3.1 channels are a target for cGMP/NO-signaling pathways following synaptic activity (Steinert et al., 2008). NO is also postulated to act as a retrograde transmitter, and although presynaptic actions are known (Garthwaite, 2008), i.e., through volume transmission (Artinian et al., 2010 and Steinert et al., 2008), the present study

focuses on signaling to postsynaptic targets. Expression of Kv3 and Kv2 channels in association with NO and glutamatergic signaling occurs broadly in the brain, including the auditory brain stem (Johnston Adenosine triphosphate et al., 2008 and Steinert et al., 2008) and hippocampus (Tansey et al., 2002). In this study nitrergic signaling was activated by sustained excitatory synaptic activity (10 Hz) for around 1 hr, modulating excitability of principal neurons in the MNTB and CA3 pyramidal neurons by suppression of Kv3 conductances and dramatic enhancement of Kv2 currents. This switched the drive for AP repolarization to Kv2 channels, raising firing threshold and altering AP responses in both brain regions. The nitrergic facilitation of Kv2 implies that this conductance is more dominant in vivo than previously suspected because recording within minutes of animal sacrifice shows vastly enhanced Kv2 currents.

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