Cyclic-Nucleotide- and HCN-Channel-Mediated Phototransduction in Intrinsically Photosensitive Retinal Ganglion Cells

Non-image-forming vision in mammals is mediated primarily by melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs). In mouse M1-ipRGCs, by far the best-studied subtype, melanopsin activates PLCβ4 (phospholipase C-β4) to open TRPC6,7 channels, mechanistically similar to phototransduction in fly rhabdomeric (microvillous) photoreceptors. We report here that, surprisingly, mouse M4-ipRGCs rely on a different and hitherto undescribed melanopsin-driven, ciliary phototransduction mechanism involving cyclic nucleotide as the second messenger and HCN channels rather than CNG channels as the ion channel for phototransduction. Even more surprisingly, within an individual mouse M2-ipRGC, this HCN-channel-dependent, ciliary phototransduction pathway operates in parallel with the TRPC6,7-dependent rhabdomeric pathway. These findings reveal a complex heterogeneity in phototransduction among ipRGCs and, more importantly, break a general dogma about segregation of the two phototransduction motifs, likely with strong evolutionary implications. [Display omitted] •Rhabdomeric and ciliary phototransductions coexist in the same cell for some ipRGCs•Unique among photoreceptor types, basic transduction traits vary in ipRGC subtypes•IpRGCs use HCN instead of CNG channels for ciliary phototransduction•The self-regulating property of HCN channels may be important for ipRGC signaling Discovery in retinal ganglion cells of a ciliary phototransduction pathway that uses cyclic nucleotide as the second messenger and HCN as the effector ion channel has evolutionary implications.