Melanopsin (Opn4) utilizes Gαi and Gβγ as major signal transducers.

Melanopsin (Opn4), a ubiquitously expressed photoreceptor in all classes of vertebrates, is crucial for both visual and non-visual signaling. Opn4 supports visual functions of the eye by sensing radiance levels and discriminating contrast and brightness. Non-image-forming functions of Opn4 not only regulate circadian behavior, but also control growth and development processes of the retina. It is unclear how a single photoreceptor could govern such a diverse range of physiological functions; a role in genetic hardwiring could be one explanation, but molecular and mechanistic evidence is lacking. In addition to its role in canonical Gq pathway activation, here we demonstrate that Opn4 efficiently activates Gi heterotrimers and signals through the G protein βγ. Compared with the low levels of Gi pathway activation observed for several Gq-coupled receptors, the robust Gαi and Gβγ signaling of Opn4 led to both generation of PIP3 and directional migration of RAW264.7 macrophages. We propose that the ability of Opn4 to signal through Gαi and Gβγ subunits is a major contributor to its functional diversity.