Vita Sereikaité

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PPIs are crucial for most cellular and biochemical process and represent a novel and promising class of drug targets. γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system (CNS), mediating slow synaptic inhibition via activation of pre- and postsynaptic receptors. It has been shown that GABA_BRs are involved in cell growth and survival, as well as, in the differentiation, migration and axon guidance of nerve cells. Consequently, GABA_BR dysfunction has been implicated in severe neurological disorders such as epilepsy, spasticity, depression, anxiety, schizophrenia and cognitive deficits. However, therapeutics targeting GABA_BRs are limited and baclofen (Lioresal^®), used to treat spasticity, remains the only approved drug targeting the GABA_BR, but serious adverse effects limit its broader use. However, much of the functional diversity observed in GABA_BR is believed to arise from the interaction with a range of receptor-associated intracellular partner proteins. More specifically, recently functional proteomics studies have revealed that GABA_BRs in rodent brains are high-molecular weight complexes consisting of two GABA_BR subunits (GABA_B1R, GABA_B2R) and a subfamily of the KCTD proteins (KCTD8/12/12b/16). KCTDs are soluble proteins that bind directly to the C-terminus of GABA_BR subunit 2 (GABA_B2R) to stabilize G protein binding, and furthermore, KCTDs interact directly with G protein subunits to modulate canonical GABA_BR downstream signaling pathways.