Melanopsin (Opn4) utilizes Gα_i 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 G_q pathway activation, here we demonstrate that Opn4 efficiently activates G_i heterotrimers and signals through the G protein βγ. Compared with the low levels of G_i pathway activation observed for several G_q-coupled receptors, the robust Gα_i 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 Gα_i and Gβγ subunits is a major contributor to its functional diversity.