Antinociceptive modulation by the adhesion GPCR CIRL promotes mechanosensory signal discrimination

Abstract

Adhesion-type GPCRs (aGPCRs) participate in a vast range of physiological processes. Their frequent association with mechanosensitive functions suggests that processing of mechanical stimuli may be a common feature of this receptor family. Previously, we reported that the Drosophila aGPCR CIRL sensitizes sensory responses to gentle touch and sound by amplifying signal transduction in low-threshold mechanoreceptors (Scholz et al., 2017). Here, we show that Cirl is also expressed in high-threshold mechanical nociceptors where it adjusts nocifensive behaviour under physiological and pathological conditions. Optogenetic in vivo experiments indicate that CIRL lowers cAMP levels in both mechanosensory submodalities. However, contrasting its role in touch-sensitive neurons, CIRL dampens the response of nociceptors to mechanical stimulation. Consistent with this finding, rat nociceptors display decreased Cirl1 expression during allodynia. Thus, cAMP-downregulation by CIRL exerts opposing effects on low-threshold mechanosensors and high-threshold nociceptors. This intriguing bipolar action facilitates the separation of mechanosensory signals carrying different physiological information.

PACmn for improved optogenetic control of intracellular cAMP

“…Albeit low, the dark activity of bPAC(wt) 0.057 min -1 (0.0009 s -1 ) is sufficient to increase resting cAMP in the absence of light, in agreement with other reports [44,52,53]. In consequence, about 25% of Drosophila larvae display nocifensive-like bending behavior in the absence of Fig.…”

“…3B), consistent with nociceptor sensitization by cAMP. Notably, the larvae also displayed spontaneous bending in the dark, likely due to the dark activity of bPAC(wt) [13,44]. This undesirable dark phenotype was removed in larvae expressing the new variants (Fig.…”

“…Drosophila larvae show stereotyped behavioral responses to noxious mechanical insult, most notably the "corkscrew" body roll, a rapid rotation along the animal's long axis, which can be triggered by stimulation with a von Frey filament or direct C4da neuron activation [42,43]. Recent work showed that optogenetic cAMP production by bPAC sensitizes C4da neurons and promotes nocifensive behavior [44]. We therefore expressed the bPAC variants in C4da neurons (ppk-GAL4 driver) and quantified nocifensive responses as an in vivo readout for cAMP production.…”

“…The nocifensive behavioral response was as described in Dannhäuser et al 2020 [44]. Wandering thirdinstar larvae were placed in a drop of water on a Sylgard-coated Petri dish and observed through a stereomicroscope (Leica M80).…”

Ligands and Beyond: Mechanosensitive Adhesion GPCRs

“…In addition to the enhancing effect on the low-threshold mechanosensory neurons responsible for gentle touch, sound, and proprioceptive input, Dannhäuser et al recently showed that dCirl is also expressed in high-threshold mechanical neurons that respond to strong mechanical stimuli [119]. Interestingly, however, dCirl exerts an opposite effect on the nociceptive neurons by dampening their response to mechanical stimulation.…”