Transmembrane AMPA receptor regulatory protein gamma 8-associated AMPA receptors (TARP gamma-8 associated AMPARs)

Transmembrane AMPA receptor regulatory protein (TARP) gamma-8-associated AMPA receptors are a specific subclass of ionotropic glutamate receptors defined by their association with the auxiliary subunit CACNG8 (gamma-8) [NIH: 16222232]. This subunit is highly enriched in the forebrain, particularly the hippocampus, where it plays a critical role in regulating the trafficking, surface expression, and biophysical gating properties of AMPA receptors [NIH: 16222232, 201912451]. Unlike other TARPs like gamma-2 (stargazin), which is prevalent in the cerebellum, gamma-8's restricted expression pattern makes it an attractive target for region-specific pharmacological intervention [NIH: 27821804]. Drugs targeting this complex, known as gamma-8 TARP-dependent AMPA receptor antagonists (TDAAs), such as LY3130481 (CERC-611), offer a therapeutic advantage in treating conditions like epilepsy and chronic pain by providing efficacy without the motor-related side effects (e.g., ataxia, dizziness) associated with non-selective AMPA receptor antagonists [NIH: 27821804, 30910921]. Beyond epilepsy, research suggests these receptors are involved in the neuroplasticity underlying alcohol use disorder and psychiatric conditions like ADHD and antisocial personality disorder [NIH: 34099853, 34101114]. The development of selective modulators for this complex represents a significant advancement in neuropharmacology, allowing for the manipulation of specific neural circuits while minimizing off-target effects in other brain regions [NIH: 27821804].

Other names

TARP gamma-8 associated AMPA receptorsgamma-8/AMPAR complexCACNG8-associated AMPA receptorsGluA1/2-gamma-8 receptorgamma-8 TARP-dependent AMPA receptors

Selective negative allosteric modulation of AMPA receptors associated with the TARP gamma-8 auxiliary subunit