Depolarizing bipolar cell dysfunction due to a Trpm1 point mutation

Neal S. Peachey, Jillian N. Pearring, Pasano Bojang, Matthew E. Hirschtritt, Gwen Sturgill-Short, Thomas A. Ray, Takahisa Furukawa, Chieko Koike, Andrew F.X. Goldberg, Yin Shen, Maureen A. McCall, Scott A Nawy, Patsy M. Nishina, Ronald G. Gregg

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Mutations in TRPM1 are found in humans with an autosomal recessive form of complete congenital stationary night blindness (cCSNB). The Trpm1-/- mouse has been an important animal model for this condition. Here we report a new mouse mutant, tvrm27, identified in a chemical mutagenesis screen. Genetic mapping of the no b-wave electroretinogram (ERG) phenotype of tvrm27 localized the mutation to a chromosomal region that included Trpm1. Complementation testing with Trpm1-/- mice confirmed a mutation in Trpm1. Sequencing identified a nucleotide change in exon 23, converting a highly conserved alanine within the pore domain to threonine (p.A1068T). Consistent with prior studies of Trpm1-/- mice, no anatomical changes were noted in the Trpm1tvrm27/tvrm27 retina. The Trpm1tvrm27/tvrm27 phenotype is distinguished from that of Trpm1-/- by the retention of TRPM1 expression on the dendritic tips of depolarizing bipolar cells (DBCs). While ERG b-wave amplitudes of Trpm1+/- heterozygotes are comparable to wild type, those of Trpm1+/tvrm27 mice are reduced by 32%. A similar reduction in the response of Trpm1+/tvrm27 DBCs to LY341495 or capsaicin is evident in whole cell recordings. These data indicate that the p.A1068T mutant TRPM1 acts as a dominant negative with respect to TRPM1 channel function. Furthermore, these data indicate that the number of functional TRPM1 channels at the DBC dendritic tips is a key factor in defining DBC response amplitude. The Trpm1tvrm27/tvrm27 mutant will be useful for elucidating the role of TRPM1 in DBC signal transduction, for determining how Trpm1 mutations impact central visual processing, and for evaluating experimental therapies for cCSNB.

Original languageEnglish (US)
Pages (from-to)2442-2451
Number of pages10
JournalJournal of Neurophysiology
Volume108
Issue number9
DOIs
StatePublished - Nov 1 2012

Fingerprint

Point Mutation
Mutation
LY 341495
Phenotype
Investigational Therapies
Capsaicin
Patch-Clamp Techniques
Threonine
Heterozygote
Mutagenesis
Alanine
Dendritic Cells
Retina
Exons
Signal Transduction
Nucleotides
Animal Models
Congenital stationary night blindness

Keywords

  • Congenital stationary night blindness
  • Depolarizing bipolar cell
  • Electroretinogram
  • TRP channel

ASJC Scopus subject areas

  • Neuroscience(all)
  • Physiology

Cite this

Peachey, N. S., Pearring, J. N., Bojang, P., Hirschtritt, M. E., Sturgill-Short, G., Ray, T. A., ... Gregg, R. G. (2012). Depolarizing bipolar cell dysfunction due to a Trpm1 point mutation. Journal of Neurophysiology, 108(9), 2442-2451. https://doi.org/10.1152/jn.00137.2012

Depolarizing bipolar cell dysfunction due to a Trpm1 point mutation. / Peachey, Neal S.; Pearring, Jillian N.; Bojang, Pasano; Hirschtritt, Matthew E.; Sturgill-Short, Gwen; Ray, Thomas A.; Furukawa, Takahisa; Koike, Chieko; Goldberg, Andrew F.X.; Shen, Yin; McCall, Maureen A.; Nawy, Scott A; Nishina, Patsy M.; Gregg, Ronald G.

In: Journal of Neurophysiology, Vol. 108, No. 9, 01.11.2012, p. 2442-2451.

Research output: Contribution to journalArticle

Peachey, NS, Pearring, JN, Bojang, P, Hirschtritt, ME, Sturgill-Short, G, Ray, TA, Furukawa, T, Koike, C, Goldberg, AFX, Shen, Y, McCall, MA, Nawy, SA, Nishina, PM & Gregg, RG 2012, 'Depolarizing bipolar cell dysfunction due to a Trpm1 point mutation', Journal of Neurophysiology, vol. 108, no. 9, pp. 2442-2451. https://doi.org/10.1152/jn.00137.2012
Peachey NS, Pearring JN, Bojang P, Hirschtritt ME, Sturgill-Short G, Ray TA et al. Depolarizing bipolar cell dysfunction due to a Trpm1 point mutation. Journal of Neurophysiology. 2012 Nov 1;108(9):2442-2451. https://doi.org/10.1152/jn.00137.2012
Peachey, Neal S. ; Pearring, Jillian N. ; Bojang, Pasano ; Hirschtritt, Matthew E. ; Sturgill-Short, Gwen ; Ray, Thomas A. ; Furukawa, Takahisa ; Koike, Chieko ; Goldberg, Andrew F.X. ; Shen, Yin ; McCall, Maureen A. ; Nawy, Scott A ; Nishina, Patsy M. ; Gregg, Ronald G. / Depolarizing bipolar cell dysfunction due to a Trpm1 point mutation. In: Journal of Neurophysiology. 2012 ; Vol. 108, No. 9. pp. 2442-2451.
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