Abstract
Adhesion-type G protein-coupled receptors (aGPCRs), a large molecule family with over 30 members in humans, operate in organ development, brain function and govern immunological responses. Correspondingly, this receptor family is linked to a multitude of diverse human diseases. aGPCRs have been suggested to possess mechanosensory properties, though their mechanism of action is fully unknown. Here we show that the Drosophila aGPCR Latrophilin/dCIRL acts in mechanosensory neurons by modulating ionotropic receptor currents, the initiating step of cellular mechanosensation. This process depends on the length of the extended ectodomain and the tethered agonist of the receptor, but not on its autoproteolysis, a characteristic biochemical feature of the aGPCR family. Intracellularly, dCIRL quenches cAMP levels upon mechanical activation thereby specifically increasing the mechanosensitivity of neurons. These results provide direct evidence that the aGPCR dCIRL acts as a molecular sensor and signal transducer that detects and converts mechanical stimuli into a metabotropic response.
Highlights
Sensory strategies for the perception of mechanical cues are essential for survival
To obtain a translational expression profile of dCIRL, we constructed a genomic transgene that contains an mRFP cassette inserted into an exon encoding part of the extracellular domain (ECD) of the receptor at a position where its folding and trafficking should not be affected (Scholz et al, 2015)
structured illumination microscopy (SIM) images depicted a patchy distribution of dCIRLN-RFP at the membrane of the lch5 dendrite and cilium, where it localized near the Transient Receptor Potential (TRP) channel TRPN1/NompC (Yan et al, 2013; Zhang et al, 2015) (Figure 1c)
Summary
Sensory strategies for the perception of mechanical cues are essential for survival. our understanding of the underlying molecular mechanisms is far from complete. Several aGPCRs have recently been linked to mechanosensitive functions (Petersen et al, 2015; Scholz et al, 2015; White et al, 2014). These examples collectively suggest that processing of mechanical stimuli may be a common feature of this receptor family (Langenhan et al, 2016). Lengthening dCIRL’s N-terminal fragment (NTF) gradually reduces mechanosensory neuronal responses. This is consistent with a model in which mechanical tension applied to the receptor determines the extent of its activity. We show that mechanical stimuli effect a dCIRL-dependent decrease of cAMP levels in ChO neurons
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