International Union of Basic and Clinical Pharmacology. CXX. γ-Hydroxybutyrate protein targets in the mammalian brain-beyond classic receptors.

γ-Hydroxybutyrate (GHB) is a multifaceted compound with an intriguing, yet undeciphered, pharmacology in the mammalian brain. As a metabolite of GABA it is tightly regulated in terms of synthesis and degradation, and is found in micromolar concentrations in the brain. When GHB is taken in high pharmacological doses, it causes euphoria, relaxation, hypothermia, and sedation, and regulates sleep. Through careful pharmacological and genetic studies, this profile has been convincingly matched to the metabotropic GABA receptor where GHB is a weak agonist. These effects explain the illicit substance use of GHB, but also its clinically useful effects as a drug in alcoholism and narcolepsy. Additionally, GHB binds with high affinity to a discrete binding site with high expression in the forebrain, and with very well defined anatomical, biochemical, and pharmacological characteristics. Despite this clear profile, the molecular identity of this binding protein or alleged "GHB receptor" has remained uncertain. However, recently, prompted by the development of GHB analogs with low nanomolar affinity and selectivity for the high-affinity site, the target was revealed to be the Ca/calmodulin (CaM)-dependent protein kinase II alpha subunit-a highly important brain kinase, mediating both physiological processes in synaptic plasticity, and detrimental Ca signaling and cell death in cases of brain ischemia. The discovery of calmodulin-dependent protein kinase II alpha subunit as the high-affinity brain target for GHB represents a major leap forward in our understanding of GHB neurobiology, and dictates new times for GHB research, suggesting a potential role for GHB and GHB analogs as integrators of inhibitory and excitatory brain signaling. SIGNIFICANCE STATEMENT: γ-Hydroxybutyrate is a molecule with a multitude of actions in the mammalian brain, and with a rather complex molecular pharmacology. A low affinity at GABA receptors, located mainly at inhibitory synapses, and a high affinity at the Ca2+/CaM-dependent protein kinase II alpha subunit, located at excitatory synapses, makes GHB pharmacology especially intriguing.