Depolarizing bipolar cell dysfunction due to a Trpm1 point mutation.

Authors

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 Nawy
Patsy M NishinaFollow
Ronald G Gregg

Document Type

Article

Publication Date

11-1-2012

JAX Location

Reprint Collection

JAX Source

J Neurophysiol 2012; 108:2442-2451.

PMID

22896717

Volume

108

Issue

9

First Page

2442

Last Page

2451

ISSN

1522-1598

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 Trpm1(tvrm27/tvrm27) retina. The Trpm1(tvrm27/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 Trpm1(tvrm27/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.

Recommended Citation

Peachey N, Pearring J, Bojang P, Hirschtritt M, Sturgill-Short G, Ray T, Furukawa T, Koike C, Goldberg A, Shen Y, McCall M, Nawy S, Nishina P, Gregg R. Depolarizing bipolar cell dysfunction due to a Trpm1 point mutation. J Neurophysiol 2012; 108:2442-2451.