Family 3 GPCRs

Family 3 recruits about two dozens GPCRs such as metabotropic glutamate receptors (mGluR), the calcium-sensing receptor, and GABAb receptors, but also potential taste, pheromone, and olfactory receptors. Like in Family 2, these receptors possess large ectodo-mains responsible for ligand binding. The homology of the ectodomain of mGluR to the leucine/isoleucine/valine-binding protein (LIVBP) and other bacterial periplasmic binding proteins that mediate the transport of amino acids in prokaryotes is obvious. Pioneering studies with GABAb receptors implicate that GPCR may exist as dimers and that dimeriza-tion may potentially play important roles in the function of these receptors (see Chapter 4.3). Recently, crystal structures of the extracellular ligand-binding region of mGluRl—in a complex with glutamate and in two non-liganded forms—have been resolved showing disulphide-linked homodimers (Kunishima etal. 2000). There was also first evidence that G proteins might not always be necessary for recruitment of signalling molecules to the receptor. Several metabotropic receptors, including members of the mGluR subfamily have proline-rich intracellular domains, suitable for direct interaction with SH2- and SH3-containing proteins. Such direct protein-protein contacts form the structural basis of potential G protein-independent signalling cascades.

Family 3 GPCRs are defined as a group of receptors comprising at least three different subfamilies that share >20% amino acid identity over their seven membrane-spanning regions. Subfamily I includes the metabotropic glutamate receptors, mGluRs 1-8, which are receptors for the excitatory neurotransmitter glutamate and are widely expressed in the central nervous system (see Chapters 4.2 and 4.3). Subfamily II contains at least two types of receptors: the calcium-sensing receptor and a recently discovered, multigene subfamily of putative pheromone receptors. Subfamily III includes a subfamily of receptors, the GABAb receptors, that bind and are activated by the inhibitory neurotransmitter GABA.

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