Relief of Mg<sup>2+</sup>-Dependent Inhibition of TRPM1 by PKCα at the Rod Bipolar Cell Synapse

Rampino, Melissa Ann F.; Nawy, Scott

doi:10.1523/jneurosci.2655-11.2011

Cited by 30 publications

(25 citation statements)

References 56 publications

(72 reference statements)

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“…A high concentration of the mGluR6 antagonist LY34149 (100 μM) was then "puffed" onto the dendrites of an ON bipolar cell, resulting in a transient displacement of L-AP4 from mGluR6, and the opening of TRPM1 channels. At physiological membrane potentials, the opening of TRPM1 produces an inward current, but we typically voltage clamp cells at positive voltages, as this tends to reduce run down of the response (18,19), and so the current generated by the opening of TRPM1 is outward. An example of the TRPM1 current generated using this approach is shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

G-protein–mediated inhibition of the Trp channel TRPM1 requires the Gβγ dimer

Shen

Rampino

Carroll

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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ON bipolar cells are critical for the function of the ON pathway in the visual system. They express a metabotropic glutamate receptor (mGluR6) that, when activated, couples to the G o class of G protein. The channel that is primarily responsible for the synaptic response has been recently identified as the transient receptor potential cation channel subfamily M member 1 (TRPM1); TRPM1 is negatively coupled to the mGluR6/Go cascade such that activation of the cascade results in closure of the channel. Light indirectly opens TRPM1 by reducing transmitter release from presynaptic photoreceptors, resulting in a decrease in mGluR6 activation. Conversely, in the dark, binding of synaptic glutamate to mGluR6 inhibits TRPM1 current. Closure of TRPM1 by G-protein activation in the dark is a critical step in the process of ON bipolar cell signal transduction, but the precise pathway linking these two events is not understood. To address this question, we measured TRPM1 activity in retinal bipolar cells, in human ependymal melanocytes (HEMs) that endogenously express TRPM1, and in HEK293 cells transfected with TRPM1. Dialysis of the Gβγ subunit dimer, but not Gα o , closed TRPM1 channels in every cell type that we tested. In addition, activation of an endogenous G-protein-coupled receptor pathway in HEK293 cells that releases Gβγ without activating Go protein also closed TRPM1 channels. These results suggest a model in which the Gβγ dimer that is released as a result of the dissociation from Gα o upon activation of mGluR6 closes the TRPM1 channel, perhaps via a direct interaction. patch clamp | calcium imaging R etinal ON bipolar cells are connected to photoreceptors through a sign-inverting synapse. At this synapse, glutamate binds to the metabotropic glutamate receptor mGluR6, which couples to the closure of a cation-selective transduction channel. Insight into the molecular identity of the transduction channel was gained from the observation that low levels of mRNA encoding the transient receptor potential ion channel TRPM1 was associated with a form of congenital stationary night blindness (CSNB) in a population of Appaloosa horses (1). Soon after, it was shown that ON bipolar cell function was absent or severely impaired in a mouse model that lacked TRPM1 expression (2-4), although there is evidence that one or more classes of cone-driven ON bipolar cells may use an additional channel (3). Mutations in TRPM1 have now been positively linked to CSNB in humans as well (5-7). Taken together, studies of mouse, horse, and human provide convincing evidence that the ON bipolar cell transduction channel is composed of TRPM1, either alone or in conjunction with other channels. However, all these studies do not provide insight into the mechanism by which activation of mGluR6 leads to closure of TRPM1.The metabotropic receptor mGluR6 preferentially couples to the G o class of G protein, both in bipolar cells (8, 9) and expression systems (10, 11). Activation of mGluR6 and, correspondingly, Go, results in closure of TRPM1. However...

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Section: Resultsmentioning

confidence: 99%

G-protein–mediated inhibition of the Trp channel TRPM1 requires the Gβγ dimer

Shen

Rampino

Carroll

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…7). The variability in response waveform is reflective of our experience across multiple studies (Rampino et al 2011;Shen et al 2009Shen et al , 2012 and may reflect variability in diffusion characteristics of individual puffs as well as the location of the puffer pipette with respect to the membrane patch being analyzed. In comparison, responses of Trpm1 tvrm27/tvrm27 DBCs under these conditions were indistinguishable from background noise (Fig.…”

Section: Resultsmentioning

confidence: 99%

Depolarizing bipolar cell dysfunction due to a Trpm1 point mutation

Peachey

Pearring

Bojang

et al. 2012

Journal of Neurophysiology

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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.

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“…After activation, TRPM1 desensitizes and the light response decays (Morgans et al, 2009;Koike et al, 2010). The synaptic efficiency of the rod-bipolar cells is regulated via modulation of a block by Mg 2+ of TRPM1 via DAG, PIP 2 , and PKCa (Rampino and Nawy, 2011).…”

Section: +mentioning

confidence: 99%