Inhibitory G_i/O-coupled receptors in somatosensory neurons: Potential therapeutic targets for novel analgesics

Abstract

Primary sensory neurons in the dorsal root ganglia and trigeminal ganglia are responsible for sensing mechanical and thermal stimuli, as well as detecting tissue damage. These neurons express ion channels that respond to thermal, mechanical, or chemical cues, conduct action potentials, and mediate transmitter release. These neurons also express a large number of G-protein coupled receptors, which are major transducers for extracellular signaling molecules, and their activation usually modulates the primary transduction pathways. Receptors that couple to phospholipase C via heterotrimeric Gq/11 proteins and those that activate adenylate cyclase via Gs are considered excitatory; they positively regulate somatosensory transduction and they play roles in inflammatory sensitization and pain, and in some cases also in inducing itch. On the other hand, receptors that couple to Gi/o proteins, such as opioid or GABAB receptors, are generally inhibitory. Their activation counteracts the effect of Gs-stimulation by inhibiting adenylate cyclase, as well as exerts effects on ion channels, usually resulting in decreased excitability. This review will summarize knowledge on Gi-coupled receptors in sensory neurons, focusing on their roles in ion channel regulation and discuss their potential as targets for analgesic and antipruritic medications.

Gi-Coupled Receptor Activation Potentiates Piezo2 Currents via Gβγ

“…After recording the basal RA-MA currents, the cells were treated with 25 µM baclofen for 3 mins and RA-MA currents were re-recorded for comparison. As expected, activation of GABAB receptors also potentiated Piezo2 currents almost 2-fold ( Figure 1C-E), in 59 % of the neurons, and had no effect in 41%% of DRG neurons tested ( Figure 1F) probably because not every DRG neuron co-expresses GABAB1 and GABAB2 receptors and the obligatory heterodimerization of these receptors is required for proper Gprotein signaling (Padgett and Slesinger, 2010;Yudin and Rohacs, 2018). In both protocols, baclofeninduced potentiation was long lasting and persisted for several minutes after removal of the agonist ( Fig.…”

“…Gi-coupled receptor activation leads to the dissociation of the trimeric G-proteins: Gαi and Gβγ. Since most of the documented effects on ion channels after activation of the Gi-signaling pathway are attributed to Gβγ (Yudin and Rohacs, 2018), we tested if the regulation of Piezo channels was mediated by Gβγ. We showed that co-expression of βARKct, which chelates Gβγ, abolished both the potentiation of Piezo2, and the inhibition of Piezo1, after activation of Gi-coupled receptors ( Fig.…”

“…It has been well documented that the peripheral activation of Gi-coupled receptors in DRG neurons may induce hyperalgesia and promote mechanical pain (Araldi et al, 2016(Araldi et al, , 2018Yudin and Rohacs, 2018). Intradermal hind paw injection of the migraine drug sumatriptan for example evoked both an acute hyperalgesia 30 minutes after its injection, and hyperalgesic priming, potentiating the effect of PGE2, an effect that developed several days after the injection of the drug (Araldi et al, 2016).…”

“…Many different Gi-coupled receptors, such as GABAB and opioid receptors are expressed in DRG neurons; their activation generally reduces excitability, and exert analgesic effects (Yudin and Rohacs, 2018). Activation of many Gi-coupled receptors however was shown to induce mechanical hypersensitivity, the mechanism of which is not understood (Araldi et al, 2016(Araldi et al, , 2018Yudin and Rohacs, 2018) Here we found that activation of Gi-coupled receptors potentiated native Piezo2-mediated currents in DRG neurons and heterologous expressed Piezo2 channels in HEK293 cells without affecting the number of channels at the plasma membrane. Surprisingly, the currents of the closely related Piezo1 channels were inhibited after activation of Gi-coupled receptors in HEK293 cells.…”

The Emerging Role of Gβ Subunits in Human Genetic Diseases

“…According to functional and structural homologies of their α subunit, heterotrimeric G-proteins are divided into four types (Gα s , Gα i/o , Gα q/11 , and Gα 12/13 ). Each Gα defines the unique Gαβγ mediated cellular responses [1,[13][14][15][16]. Gα s and Gα i subfamily members are involved in the modulation of the intracellular second-messenger cAMP levels, either stimulating (G s ) or inhibiting (G i ) the production of cAMP by AC activity.…”