TY - JOUR
T1 - Cyclic-Nucleotide- and HCN-Channel-Mediated Phototransduction in Intrinsically Photosensitive Retinal Ganglion Cells
AU - Jiang, Zheng
AU - Yue, Wendy W.S.
AU - Chen, Lujing
AU - Sheng, Yanghui
AU - Yau, King Wai
N1 - Funding Information:
We thank L. Cao (Peking University) for rod-suction-pipette recordings to test the drug, ZD7288 and T. Xue (University of Science and Technology China) for initiating some mouse breeding and suggesting the dominant-negative strategy. We thank T.D. Lamb (Australian National University) for discussion on photoreceptor evolution, R. Payne (Univeristy of Maryland, College Park) for discussion and unpublished information about the Limulus ve/ntral photoreceptor and Ulrich Müller and Seth Blackshaw for advice on in situ hybridization. We are grateful to the following individuals for providing knockout mouse lines: L. Birnbaumer (NIEHS, Trpc1 −/− , Trpc3 −/− , Trpc6 −/− ), D.E. Clapham (HHMI Janelia Campus, Trpc7 −/− ), D. Difrancesco (University of Milan, Hcn4 fl / fl , although eventually not used; see STAR Methods ), C. Dulac (Harvard University, Trpc2 −/− ), M. Freichel (University of Saarland, Trpc4 −/− , Trpc5 −/− ), S. Kuegler (University of Goettingen, AAV6-Epac1-cAMP), S. Siegelbaum (Columbia University, Hcn1 −/− ), A. Ludwig (University of Erlangen, Hcn2 −/− , Hcn4 fl / fl ), J. Nathans (Johns Hopkins, rd / rd ), S. Offermanns (Max-Planck Institute, G α q fl / fl ;G α 11 −/− ), R. Reed (Johns Hopkins, main olfactory epithelium cross-sections and CNGA2 cDNA), N. Ryba (NIH/NIDCR, Plcβ2 −/− ), H.-S. Shin (Korea Institute of Science and Technology, Plcβ1 −/− ), M.I. Simon (Caltech, G α 14 −/− , Plcβ3 −/− , Plcβ4 −/− ), and T. Wilkie (UT Southwestern Medical Center, G α 15 −/− ). We are also grateful to the following individuals for antibodies: M. Biel (University of Munich, anti-CNGA3, anti-CNGA4, anti-CNGB3), R.S. Molday (University of British Columbia, anti-CNGA1, anti-CNGA2, anti-CNGB1), and F. Müller (Center Advanced European Studies & Research, anti-HCN4, although not providing clear-cut results). We thank T. Shelley for fabricating all custom equipment; L. Ding for mouse-genotyping support; and R. Li, X. Li, and D. Silverman in the Yau lab for comments. Finally, we thank NINDS Multi-photon Imaging Core at JHMI (P30 NS050274) for imaging and data analysis. This work was supported by NIH ( EY014596 ), the António Champalimaud Vision Award, Portugal (to K.-W.Y.), a NARSAD Young Investigator Grant (to Z.J.), and an HHMI International Predoctoral Fellowship (to W.W.S.Y.).
Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2018/10/18
Y1 - 2018/10/18
N2 - 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. 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.
AB - 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. 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.
KW - HCN channel
KW - ciliary phototransduction
KW - cyclic-nucleotide pathway
KW - ipRGCs
KW - melanopsin
KW - photoreceptors
KW - phototransduction
KW - retinal ganglion cells
KW - rhabdomeric phototransduction
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U2 - 10.1016/j.cell.2018.08.055
DO - 10.1016/j.cell.2018.08.055
M3 - Article
C2 - 30270038
AN - SCOPUS:85055064482
SN - 0092-8674
VL - 175
SP - 652-664.e12
JO - Cell
JF - Cell
IS - 3
ER -