Metabotropic glutamate receptor 6

L-glutamate is the major excitatory neurotransmitter in the central nervous system and activates both ionotropic and metabotropic glutamate receptors. Glutamatergic neurotransmission is involved in most aspects of normal brain function and can be perturbed in many neuropathologic conditions. The metabotropic glutamate receptors are a family of G protein-coupled receptors, that have been divided into 3 groups on the basis of sequence homology, putative signal transduction mechanisms, and pharmacologic properties. Group I includes GRM1 and GRM5 and these receptors have been shown to activate phospholipase C. Group II includes GRM2 and GRM3, while Group III includes GRM4, GRM6, GRM7 and GRM8. Group II and III receptors are linked to the inhibition of the cyclic AMP cascade but differ in their agonist selectivities.

mGluR6 is specifically expressed in the retina, in a subtype of bipolar cells that depolarize in response to light, known as ON bipolar cells. These cells form synapses with photoreceptor cells, and detect the neurotransmitter glutamate via a GPCR signal transduction cascade. The glutamate receptor mGluR6 is located post-synaptically at the tips of the bipolar cell dendrites, and is responsible for initiating a signaling cascade that ultimately controls gating of the TRPM1 channel. In human patients, mutations in the GRM6 gene are associated with congenital stationary night blindness.

Compounds L-AP4 and 1-benzyl-APDC act as selective agonists of group III mGluRs and mGlu₆ receptors, respectively.

A small library of photoswitchable agonists-positive allosteric modulators of mGlu₆ receptors ('prosthe6') has been developed. Their light-dependent (photopharmacological) activity in ON bipolar cells mimics the physiological signaling of the retina and allows restoring vision in animal models of retinal degeneration. In particular, they restore visually guided behavior in mouse models of macular degeneration and retinitis pigmentosa, and restore visual acuity in blinded zebrafish larvae.