In the retina, cones contact two types of bipolar cells, releasing the same transmitter onto each. Since the two types of bipolar cells must respond to light (and therefore cone transmitter) with opposite polarities, each has evolved very different postsynaptic mechanisms to solve this problem. The OFF bipolar cell expresses ionotropic α-amino-β-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) and kainate glutamate receptors, conferring depolarization during photoreceptor transmitter release. However, the requirement for a hyperpolarizing action of glutamate at ON bipolar cells ruled out the use of ionotropic receptors at this synapse. Years of investigation by a number of different laboratories have revealed this highly novel, perhaps unique mechanism by which activation of a glutamate receptor, metabotropic glutamate receptor type 6 (mGluR6), results in membrane hyperpolarization. The photoreceptor-ON bipolar cell synapse must also be adaptive, enhancing rapid changes in illumination while attenuating slower, more long-lasting changes in order to avoid saturation of downstream synapses. Calcium appears to play a major role in this form of short-term plasticity. Finally, recent evidence suggests that the gain of this synapse is additionally regulated by ambient light levels. Both cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) and protein kinase C (PKC) appear to play key roles in these forms of long-term plasticity. Sections "ON Bipolar Cells and the mGluR6 Pathway: A Brief History" and "Elucidation of the mGluR6 Signaling Cascade" of this chapter summarize what is currently known about this synaptic pathway, with an emphasis on the major historical breakthroughs that shaped our understanding of this exceedingly complex synapse along the way. Sections "Modulation of the mGluR6 Cascade: Ca2+", "Modulation of the mGluR6 Cascade: cGMP", and "Modulation of the mGluR6 Cascade: PKC and DAG" summarize the roles of Ca2+, cGMP, and PKC in the regulation of this pathway.
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