GABAB Receptors-Associated Proteins: Potential Drug Targets in Neurological Disorders?

Rafael      Lujan; Francisco      Ciruela

Abstract

γ-aminobutyric acid type B (GABAB) receptors play a critical role in neuronal excitability and modulation of synaptic neurotransmission in the central nervous system. They are G protein-coupled receptors that signal primarily through activation of G proteins (i.e. pertussis toxin sensitive Gαi/o family) to modulate the function of inwardly-rectifying K+ and voltage-gated Ca2+ channels, and to trigger cyclic adenosine monophosphate cascades. Functional GABAB receptors are obligated heterodimers formed by the co-assembly of two subunits, the GABAB1 and the GABAB2, which interact via coiled-coil domains in their C-terminal tails. It is now quite well established that GABAB receptors interact not only with heterotrimeric G proteins and effector ion channels but also with a plethora of accessory proteins that might impinge into the receptors biology. Indeed, these proteins have been implicated in several key functional aspects of the receptor, namely to link functional GABAB receptors with components of the relevant signalling pathways, to target the receptor into specific subcellular compartments, to participate in their trafficking to and from the plasma membrane, and to regulate their signalling properties. Overall, in this review we focus on those proteins that interact with GABAB receptors. Thus, understanding how the interaction between GABAB receptors and its accessory proteins takes place will definitively open new opportunities for pharmacological tool assessment of novel therapeutic targets for the treatment of several neurological diseases involving these receptors.

Keywords: GABA, associated proteins, ion channels, scaffolding, neurological disorders, drug targets, CNS, pharmacology, signalling proteins, adenylyl cyclase, enzymes, interactome, GABAB1, GABAB2