ABSTRACT
Metabotropic, or indirectly coupled, receptors are activated by a variety of neurotransmitters or paracrine hormones in the body and are responsible for mediating the actions of more than 70 per cent of the therapeutic agents which are currently in clinical use. These receptors depend on relatively few types of G-protein to link them to their effector mechanisms. Thus, it is the unique structure and conformation of individual receptors that provides the specific and individual characteristics of ligand action. In many cases the receptor is expressed in cell membranes simply as a monomer after transcription of the protein in the endoplasmic reticulum. In some instances the receptor is expressed as a functional unit by combination of two molecules of the entire receptor linked to form a homodimer. Up to 3 years ago there was no evidence for any functional receptors that comprised two forms of the complete receptor with distinct molecular structures coupled together. But then the unique conformation of the functional GABAB receptor(s) was revealed showing that it exists as a heterodimer (White et al., 1998; Kaupmann et al., 1998a; Jones et al., 1998; Kuner et al., 1999; Ng et al., 1999). This followed the original cloning of the receptor in 1997 by Kaupmann and colleagues. However, soon after the structure was announced it became apparent that the single individual receptor subunit is not normally expressed in the plasma membrane but remains in the endoplasmic reticulum (see Couve et al., 1998). Initial thoughts were focused on the possibility of an unknown trafficking protein ‘RAMP’ (receptor activity modifying protein) being required to transport the receptor protein to the external membrane (cf. McLatchie et al., 1998). For detailed information about the structure of the GABAB receptor see Chapter 11.
