2.8.4. GPCR Regulation of K*V*1.4, K*V*3.4 and K*V*4 Channels

Neuromedin U (NMU) is a neuropeptide that decreases neuronal excitability in DRG neurons via the enhancement of I*<sup>A</sup>* currents through its actions on the NMU type 1 receptor (NMUR1, Figure 8) [251]. NMUR1 couples to G*α<sup>o</sup>* proteins, PKA and the ERK pathway in a sequential manner [251]. On the other hand, the cyclic undecapeptide urotensin-II activates the urotensin-II receptor (UTR), which couples to G*αq*/11 [252,253]. This leads to a reduction in I*<sup>A</sup>* in a dose-dependent fashion in trigeminal ganglion neurons, mediated via the activation of PKC [254]. The concomitant recruitment of ERK signaling cascade culminates in an enhanced excitability of TG neurons [254]. In rat TG neurons, the K*V*1.4, K*V*3.4, K*V*4.2 and K*V*4.3 channels are co-expressed with P2Y2 receptors [255], which in turn couple to different G proteins [256]. The application of UTP, an agonist at the P2Y2 receptor inhibits I*<sup>A</sup>* currents via the ERK pathway and enhances excitability in these neurons, an effect that can be reversed by the P2Y2 receptor antagonist suramin [255].

**Figure 8.** The so-called A-current is mediated by voltage-activated K*V*1.4, K*V*3.4, and K*V*4 channels. Activation of a G*αo*-coupled receptor (**right**) increases A-type currents via a mechanism involving the G*βγ* dimer, protein kinase A (PKA) and extracellular signal-regulated kinase (ERK). Stimulation of G*αq*/11-coupled receptors (**left**) activates phospholipase C (PLC) leading to hydrolysis of phosphatityl 4,5 bisphosphate (PIP2) to diacylglycerol (DAG) and IP3. DAG activates protein kinase C (PKC), which phosphorylates A-type channels and thus inhibits these channels. ERK is activated in parallel which also phosphorylates A-type channels and thereby decreases their function.
