*2.9. G-Protein Activated, Inwardly Rectifying Potassium Channels*

G protein activated, inwardly rectifying potassium channels (GIRK) are homo- or heterotetrameric channels formed from four different subunits (K*ir*3.1–3.4) encoded by the genes KCNJ3, KCNJ6, KCNJ9 and KCNJ5, respectively [257,258]. They are activated by pertussis toxin sensitive G proteins via binding of *βγ* dimers to the channel [257]. In addition, it has also been demonstrated that the G*α* subunit can directly bind to the channels modulating their basal activity in the absence of GPCR activation [259]. Besides their G protein-mediated modulation, it has been demonstrated several times that K*ir*3 channels bind PIP2 and that this is necessary for their function [260,261].

### GPCR Modulation of Girk Channels

Compared to their role in the CNS, data on their physiological role in DRG neurons is scarce [258]. In rat DRG neurons, co-localization of GIRK channels and *μ*-opioid receptors has been found [262]. The picture is complicated by the fact that, while all four subunits are expressed in rat and human DRG neurons [117,263], only low mRNA levels and a lack of immunostaining have been reported in mice [117]. This is corroborated by the fact that local application of DAMGO (Figure 9), a *μ*-opioid receptor agonist, is ineffective in inflammatory pain mouse models [117]. This lack of effect, however, could be overcome by expressing K*ir*3.2 in Na*V*1.8 expressing nociceptive neurons [117], demonstrating the importance of K*ir*3 channels for peripheral analgesia. These findings are contrasted by the fact that GIRK currents could be induced in a small number of about 15–20% of mouse DRG neurons by application of DAMGO [264], rendering the interpretation of mouse data difficult.

**Figure 9.** G-protein activated, inwardly rectifying K<sup>+</sup> channels (GIRK) are activated subsequent to stimulation of G*αi*/*o*-coupled receptors. The dissociated G*βγ* dimer binds directly to GIRK channels.

#### **3. Conclusions**

In this review, members of ten different ion channel families that are expressed in sensory neurons are described with respect to their contribution to nociception. Appropriate gating of these channels is subject to modulation by at least 35 different types of GPCRs, which are targeted by more than 20 separate endogenous modulators (Table 2). Thereby, GPCRs provide the largest superfamily of receptors, activation of which can mediate pro- as well as antinociceptive effects . Accordingly, these GPCRs are relevant as potential targets for analgesic drugs. However, only a few of them are currently exploited in analgesic therapy, such as opioid, cannabinoid, and CGRP receptors or prostanoid receptors as indirect targets of cyclooxygenase inhibitors. Therefore, this review should be viewed as incitement to further investigate how the modulation of ion channels via GPCRs might be tackled to provide novel pharmacotherapeutic agents for improved analgesic therapy.


**Table 2.** Endogenous ligands for GPCRs modulating ion channel function.

ASIC, acid sensing ion channel; CaCC, Ca2+-activated Cl<sup>−</sup> channel; Ca*V*, voltage-gated Ca2<sup>+</sup> channel; GIRK, G-protein activated; inwardly rectifying K<sup>+</sup> channel; K2P, two-pore K<sup>+</sup> channel; K*V*, voltage-gated K<sup>+</sup> channel; Na*V*, voltage-gated Na<sup>+</sup> channel; TRP, transient receptor potential channel; TRPA, ankyrin family; TRPM, melastatin family; TRPV, vanilloid family; BAM 8-22, bovine adrenal medulla peptide 8-22; CGRP, calcidonin-gene related peptide; CGRP-R, CGRP receptor; GABA, *<sup>γ</sup>*-amino butyric acid; ?, unknown. <sup>212</sup>

**Author Contributions:** I.S., S.R., K.S. and S.B. wrote the manuscript; I.S. performed artwork.

**Funding:** Work in the authors' laboratory was supported by the doctoral program CCHD funded by the Austrian Science Fund (FWF, W1205) and the Medical University of Vienna as well as by the inter-university cluster project "Novel scaffolds for improved antiepileptic drugs" financed by the University of Vienna and the Medical University of Vienna.

**Conflicts of Interest:** The authors declare no conflict of interest.
