Journal Article

Unusual phototransduction via cross-motif signaling from Gq to adenylyl cyclase in intrinsically photosensitive retinalganglion cells

Li, Guang, Chen, Lujing, Yau, King-Wai, Jiang, Zheng

2023

Overview

SignificanceWe describe here a mammalian ciliary phototransduction mechanism in intrinsically photosensitive retinal ganglion cells that uses cAMP as the second messenger. This is highly unusual because cGMP serves as the second messenger in nearly all ciliary phototransduction mechanisms known so far. Even more surprisingly, Gq is the active G protein upstream, which, via its Gβγq released from the active Gαq, directly stimulates adenylyl cyclase to elevate cAMP and open HCN channels, leading to a membrane depolarization. Although such unconventional cross-motif GPCR signaling has previously been described by others in biochemical experiments with heterologously expressed signaling components in cell lines, our finding demonstrates such direct Gq-to-AC signaling in a native cell with a specific function. Nonimage-forming vision in mammals is mediated primarily by melanopsin (OPN4)-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs). In mouse M1-ipRGCs, melanopsin predominantly activates, via Gαq,11,14, phospholipase C-β4 to open transient receptor 6 (TRPC6) and TRPC7 channels. In M2- and M4-ipRGCs, however, a prominent phototransduction mechanism involves the opening of hyperpolarization- and cyclic nucleotide-gated channels via cyclic nucleotide, although the upstream steps remain uncertain. We report here experiments, primarily on M4-ipRGCs, with photo-uncaging of cyclic nucleotides and virally expressed CNGA2 channels to conclude that the second messenger is cyclic adenosine monophosphate (cAMP) – very surprising considering that cyclic guanosine monophosphate (cGMP) is used in almost all cyclic nucleotide-mediated phototransduction mechanisms across the animal kingdom. We further found that the upstream G protein is likewise Gq, which via its Gβγ subunits directly activates adenylyl cyclase (AC). Our findings are a demonstration in a native cell of a cross-motif GPCR signaling pathway from Gq directly to AC with a specific function.

• Publisher: National Academy of Sciences
• Subject: Adenosine monophosphate / Adenylate cyclase / Biological Sciences / Channels / Cyclic AMP / Cyclic GMP / Cyclic nucleotides / G protein-coupled receptors / Hyperpolarization / Ion channels (cyclic nucleotide-gated) / Melanopsin / Neuroscience / Nucleotides / Phospholipase C / Photosensitivity / Phototransduction / Retinal ganglion cells / Signal transduction / Signaling / Upstream