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. Nonimage-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

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... le 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 PIP 3 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.