Intron retention of an adhesion GPCR generates 1TM isoforms required for 7TM-GPCR function

Area of Science:

• Molecular Biology
• Neuroscience
• Cell Biology

Background:

• Adhesion G protein-coupled receptors (aGPCRs) are crucial for mechanobiological processes across all organs.
• Alternative splicing in aGPCRs suggests significant molecular structural diversity.
• Conventional GPCRs possess a characteristic 7-transmembrane (7TM) signaling unit.

Purpose of the Study:

• To investigate unconventional aGPCRs in Drosophila.
• To understand the role of single-transmembrane (1TM) proteins in aGPCR signaling.
• To elucidate the mechanism linking alternative splicing to aGPCR function and interactors.

Main Methods:

• Analysis of Drosophila genome and proteome.
• Identification of intron retention events leading to 1TM protein variants.
• Biochemical assays to determine protein interactions and signaling pathways.
• In vivo studies to assess neuronal function and sensory precision.

Main Results:

• Discovery of 1TM-containing ADGRL/Cirl proteins in Drosophila, lacking the canonical 7TM domain.
• These 1TM proteins are generated via intron retention.
• The N-terminal fragment of 1TM proteins acts as an interactor for Gαo-dependent signaling.
• This interaction facilitates signaling through conventional 7TM Cirl isoforms from the same gene.
• Demonstrated enhancement of neuronal sensory precision in response to mechanical stimuli in vivo.

Conclusions:

• Alternative splicing is a key mechanism for expressing aGPCRs with integrated molecular interactors.
• Unconventional 1TM aGPCRs provide a novel mode of G protein signaling.
• This discovery offers new avenues for therapeutic and experimental interventions targeting aGPCRs.