A Chemical Screen Identifies Class A G-Protein Coupled Receptors As Regulators of Cilia

Normal cilia length and motility are critical for proper
cellular function. Prior studies of the regulation of ciliary structure
and length have primarily focused on the intraflagellar transport
machinery and motor proteins required for ciliary assembly and disassembly.
However, several mutants with abnormal length flagella highlight the
importance of signaling proteins as well. In this study, an unbiased
chemical screen was performed to uncover signaling pathways that are
critical for ciliogenesis and length regulation using flagella of
the green alga Chlamydomonas reinhardtii as a model.
The annotated Sigma LOPAC1280 chemical library was screened for effects
on flagellar length, motility, and severing as well as cell viability.
Assay data were clustered to identify pathways regulating flagella.
The most frequent target found to be involved in flagellar length
regulation was the family of dopamine binding G-protein coupled receptors
(GPCRs). In mammalian cells, cilium length could indeed be altered
with expression of the dopamine D1 receptor. Our screen thus reveals
signaling pathways that are potentially critical for ciliary formation,
resorption, and length maintenance, which represent candidate targets
for therapeutic intervention of disorders involving ciliary malformation
and malfunction.