Modulation of TRPM1 as a mechanism of gain control at the rod bipolar cell synapse
Rampino, Melissa Ann F.
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Retinal bipolar cells are the first site of information processing in the visual system. Light signals detected by photoreceptor cells are transmitted to downstream bipolar cells and information about the visual scene such as luminosity and contrast is extracted. The rod pathway of the retina transmits all dim light information, and the synapse between rods and rod bipolar cells (RBCs) is a critical site for relaying and processing visual information. In particular, processing at this synapse includes several mechanisms for adjusting the gain of rod signal transmission so the sensitivity and fidelity of the rod signal is preserved.;In the dark, rods are depolarized and steadily releasing glutamate into the synaptic cleft. Hyperpolarization of these cells at the onset of light slows the release of glutamate, causing the metabotropic glutamate receptor mGluR6 to shut off and allowing the inversely coupled RBC synaptic channel TRPM1 to open. The mGluR6-TRPM1 complex governs signaling at the RBC synapse and is therefore fundamental to proper visual processing. In this thesis I employ an electrophysiological approach to present a comprehensive examination of the regulation of TRPM1 using patch-clamp recordings from bipolar cells in a retinal slice preparation. I explore basic channel properties that dictate signal transmission at this synapse. In addition, I show that RBCs utilize the canonical phosphoinositide signaling cascade involving PIP2, PLC, and PKCalpha to modulate the gain of the RBC response and that this cascade is initiated by the metabotropic glutamate receptor mGluR1alpha. Finally, I present evidence that the balance of activation of these receptors is a function of adaptation state of the retina. This work therefore provides a model whereby TRPM1 is dually regulated by mGluR6, which is required to close the channel, and mGluR1alpha, which sets the gain of the synapse in response to ambient light levels.
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