High-affinity gamma-hydroxybutyrate receptor (GHBR)

The high-affinity gamma-hydroxybutyrate (GHB) receptor, also known as the GHB binding protein, is a distinct molecular target in the mammalian brain that binds endogenous GHB at physiological micromolar concentrations [1, 13]. Unlike the low-affinity GABA-B receptor, which mediates the sedative and anesthetic effects of high-dose GHB, the high-affinity receptor is thought to facilitate excitatory neurotransmission and neuroprotection [2, 5]. The molecular identity of this target has been a subject of significant debate, with candidates including the G-protein coupled receptor GPR172A (later identified as a riboflavin transporter), the alpha4-beta-delta (α4βδ) subtype of the GABA-A receptor, and most recently, the alpha subunit of Calcium/calmodulin-dependent protein kinase II (CaMKIIα) [2, 5, 7]. This receptor is highly expressed in the hippocampus and cortex, where it modulates the release of glutamate, dopamine, and serotonin, thereby influencing synaptic plasticity and sleep-wake homeostasis [1, 14]. Clinically, it is relevant to the pharmacology of sodium oxybate, a medication used to treat narcolepsy and alcoholism, and it is a focus of research into absence seizures and succinic semialdehyde dehydrogenase (SSADH) deficiency [12, 17]. Selective ligands such as the antagonist NCS-382 and the agonist HOCPCA are used to differentiate its effects from those of GABA receptors [4, 23]. Understanding this target is crucial for developing GHB analogs with therapeutic benefits that lack the severe sedative and addictive properties associated with GABA-B activation [1, 2].

Other names

GHB receptorGHB binding proteinGHBh1Gamma-hydroxybutyrate receptorGPR172Aalpha4beta-delta GABA-A receptorCaMKII alpha subunit

Agonism at high-affinity binding sites to modulate excitatory neurotransmission and synaptic plasticity.