title: Genetic dissection of horizontal cell inhibitory signaling in mice in complete darkness in vivo.
abstract: OBJECTIVE
  To test the hypothesis that horizontal cell (HC) inhibitory signaling controls the degree to which rod cell membranes are depolarized as measured by the extent to which L-type calcium channels (LTCCs) are open in complete darkness in the mouse retina in vivo.
  
  
  METHODS
  Dark-adapted wild-type (wt), CACNA1F (Ca(v)1.4(-/-)), arrestin-1 (Arr1(-/-)), and CACNA1D (Ca(v)1.3(-/-)) C57Bl/6 mice were studied. Manganese-enhanced MRI (MEMRI) evaluated the extent that rod LTCCs are open as an index of loss of HC inhibitory signaling. Subgroups were pretreated with D-cis-diltiazem (DIL) at a dose that specifically antagonizes Ca(v)1.2 channels in vivo.
  
  
  RESULTS
  Knockout mice predicted to have impaired HC inhibitory signaling (Ca(v)1.4(-/-) or Arr1(-/-)) exhibited greater than normal rod manganese uptake; inner retinal uptake was also supernormal. Genetically knocking out a closely associated gene not expected to impact HC inhibitory signaling (CACNA1D) did not generate this phenotype. The Arr1(-/-) mice exhibited the largest rod uptake of manganese. Manganese-enhanced MRI of DIL-treated Arr1(-/-) mice suggested a greater number of operant LTCC subtypes (i.e., Ca(v)1.2, 1.3, and 1.4) in rods and inner retina than that in DIL-treated Ca(v)1.4(-/-) mice (i.e., Ca(v)1.3). The Ca(v)1.3(-/-) + DIL-treated mice exhibited evidence for a compensatory contribution from Ca(v)1.2 LTCCs.
  
  
  CONCLUSIONS
  The data suggest that loss of HC inhibitory signaling is the proximate cause leading to maximally open LTCCs in rods, and possibly inner retinal cells, in mice in total darkness in vivo, regardless of compensatory changes in LTCC subtype manifested in the mutant mice.
authors.affiliation: Department of Anatomy and Cell Biology Wayne State University School of Medicine, Detroit, Michigan, United States 2Department of Ophthalmology, Wayne State University School of Medicine, Detroit, Michigan, United States.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Berkowitz
authors.affiliation: University of Michigan Medical School, Molecular Behavioral Neuroscience Institute, Molecular and Integrative Physiology, Ann Arbor, Michigan, United States.
authors.forename: Geoffrey G
authors.initials: GG
authors.lastname: Murphy
authors.affiliation: Mary D. Allen Laboratory for Vision Research, USC Eye Institute, and Department of Ophthalmology and Department of Cell and Neurobiology, Keck School of Medicine of the University of Southern California, Los Angeles, California, United States.
authors.forename: Cheryl Mae
authors.initials: CM
authors.lastname: Craft
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States.
authors.forename: D James
authors.initials: DJ
authors.lastname: Surmeier
authors.affiliation: Department of Anatomy and Cell Biology Wayne State University School of Medicine, Detroit, Michigan, United States.
authors.forename: Robin
authors.initials: R
authors.lastname: Roberts
mesh_terms: D000818:Animals; D019393:Arrestin / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D003623:Dark Adaptation / Q000502:physiology*; D003624:Darkness; D004110:Diltiazem / Q000494:pharmacology; D005260:Female; D008279:Magnetic Resonance Imaging; D008297:Male; D008345:Manganese / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017120:Nystagmus, Optokinetic / Q000502:physiology; D012160:Retina / Q000378:metabolism*; D051248:Retinal Horizontal Cells / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D019393:Arrestin; C485995:Cacna1d protein, mouse; C480684:Cacna1f protein, mouse; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D008345:Manganese; D004110:Diltiazem