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P. Wang, M. Slaughter; Enhanced Receptor Sensitivity Due to Receptor Desensitization. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3227.
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© ARVO (1962-2015); The Authors (2016-present)
Fast retinal neurotransmitters produce pronounced desensitization, in which the ligand is tightly bound to the receptor but does not gate the channel. It has been suggested that desensitization is neuroprotective, preventing ion loading of neurons, or that it is responsible for high pass filtering at the synapse. Most studies of receptor desensitization focus on the current response of neurons. We examined the effect of desensitization on the voltage response. We found another role for desensitization, which is to enhance postsynaptic receptor sensitivity.
Maple 10 mathematical software was used to generate models of the current and voltage responses of neurons. Ligand-gated channels were simulated by Closed-Open-Desensitized schemes in which the forward and backward rates could be varied, as well as the concentration of agonist. These models were compared to responses of fast and slow desensitizing glycine receptors.
Receptor desensitization leads to a suppression of the current response and a similar but less pronounced decrease in the voltage response. Many ionotropic ligands activate both fast activating/fast desensitizing receptors and slow activating/slow desensitizing receptors. We tested the hypothesis that combined input from these two receptors would endow the synapse with the capability to rapidly change voltage and then switch to a lower current mode for sustained signaling. However, this combined receptor input provided very little advantage. Unexpectedly, we found that desensitized responses had a lower EC50 than the peak, non-desensitized response. Thus, paradoxically, the desensitized receptor is more sensitive to changes in presynaptic transmitter concentration.
Even as the postsynaptic response amplitude declines during desensitization, the differential response of postsynaptic neurons to neurotransmitter concentration is enhanced. This postsynaptic process occurs at the same time that the presynaptic cell is reducing its vesicular release. Therefore, the postsynaptic cell is less transmitter-sensitive at a time when presynaptic release is high, and then become more sensitive to changes in transmitter level as presynaptic release declines. This suggests a novel role for postsynaptic receptor desensitization in signal discrimination during a time of presynaptic vesicle depletion.
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