*2.6. GPCR Regulation of Voltage-Gated Na*<sup>+</sup> *Channels*

The activity of TTX-resistant voltage-gated Na<sup>+</sup> channels is affected by activation of G*α<sup>s</sup>* coupled receptors (Figure 5). Direct activation of adenylyl cyclase by forskolin increases TTX-resistant Na<sup>+</sup> currents in dorsal root ganglion neurons. Activation of adenylyl cyclase increases the formation of cAMP, which wash shown to be involved in this process [158]. In sensory neurons, the inflammatory mediators serotonin [158], PGE2 [159,160] and CGRP [161] were found increase TTX-resistant Na<sup>+</sup> currents via a mechanism involving G*αs*-coupled 5-HT4 [162,163], EP4 [164], and CGRP [161] receptors, respectively. Application of substance P leads to an increase in neuronal excitability in small diameter dorsal root ganglion neurons [165]. Substance P activates neurokinin 1 (NK1) receptors, amongst others [110]. These G*αs*- and G*αq*-coupled receptors were found to increase TTX-resistant Na<sup>+</sup> currents in dorsal root ganglion neurons in a PKC dependent manner [166]. In addition, ATP, another component of the inflammatory soup, was also found to increase TTX-resistant Na<sup>+</sup> currents in sensory neurons. By contrast, TTX-sensitive currents were not affected by application of ATP [167]. The underlying signaling cascade was not elucidated and hence it remains to be determined if, for example, G*αs*-coupled P2Y11 receptors could be involved.

On the other hand, activation of protease activated receptor 2 (PAR2) does not affect TTX-resistant Na<sup>+</sup> currents in nociceptive neurons [168]. These GPCRs are coupled to heterotrimeric G*αq*-proteins and lead to release of Ca2<sup>+</sup> from intracellular stores as well as activation of PKC [142].

With respect to G*αi*/*o*-coupled receptors, only activation of *μ*-opioid receptors by the agonist DAMGO was investigated. In sensory neurons, application of DAMGO was able to prevent the PGE2-mediated increase of TTX-resistant Na<sup>+</sup> channels [169]. The involved pathway was not investigated, but is seems reasonable to assume an interference of the G*αi*/*o*-pathway with the G*αs*-mediated potentiation of these NaV channels.

**Figure 5.** Na*V*1.x channels are activated by depolarizing voltages (as indicated). Activation of G*αs*-coupled receptors stimulates adenylyl cyclase (AC) activity (**center**). Subsequently, cyclic adenosine monophosphate (cAMP) is formed, which activates protein kinase A (PKA). PKA-mediated phosphorylation of voltage-gated Na<sup>+</sup> channels increases their currents. By contrast, activation of G*αi*/*o*-coupled receptors (**right**) decreases AC activity and counteracts G*αs*-mediated current increases. Activation of a G*αq*/11-receptor (**left**)was shown to increase Na*V*-mediated currents involving protein kinase C (PKC).
