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J. Snellman, S. Nawy; Use-dependent Modulation of the mGluR6 Pathway in Mouse . Invest. Ophthalmol. Vis. Sci. 2003;44(13):1005.
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Purpose: We have previously shown that the On-Bipolar cell mGluR6-elicited current depresses in a use-dependent manner, and that this depression is mediated by calcium and calcineurin. Here, we report on a second mechanism of depression, which is modulated on a faster time scale. This study aims to characterize this fast depression and its site of action. Methods: Whole cell recordings were performed on voltage clamped On-Bipolar cells in mouse retinal slices bathed in 2µM APB (Group III mGluR agonist). Responses were obtained by fast superfusion of the group III mGluR antagonist CPPG (300µM) via flowpipes. Results: We pharmacologically mimicked the presentation of light flashes by continuously bathing On bipolar cells with APB, which holds the cation channel closed, and then briefly applying CPPG, which results in the opening of the cation channel. During the application of CPPG, the cation current depressed over a period as brief as 30 seconds. The depression was associated with a decrease in current noise, and a change in the baseline current, indicating that the depression was due to a decrease in channel openings during CPPG application. A decrease in the magnitude of the cation current could be due to the influx of calcium through the channel, although the depression occurred at holding potentials of +50mV as well as -50mV and was insensitive to dialysis with BAPTA. The response to CPPG could be restored by a10 min wash with 2µM APB. This suggests that the recovery depends upon the cation channel remaining closed, as it is in darkness. The recovery was associated with an increase in current noise, suggesting that the10 minute application of APB is sufficient to restore channel function. Conclusion: The On-bipolar cell current depresses in a use-dependent manner, and is regulated by at least two superimposed processes. One, short term process, is BAPTA insensitive, appears to act directly on the channel, and can be restored. The second process, which we have published on previously, is slower, possibly modulating coupling of the receptor and cation channel, is not recoverable with conventional whole-cell recording, and can be prevented by buffering calcium by BAPTA. We propose that these mechanisms act together to regulate the function of the mGluR6 pathway.
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