Voltage-dependent calcium channel subunit gamma-8 (CACNG8)

The Voltage-dependent calcium channel subunit gamma-8 (CACNG8), commonly known as TARP gamma-8, is a transmembrane protein that serves as a critical auxiliary subunit for Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the brain (UniProt, P60745). Unlike other TARPs, gamma-8 is highly enriched in the hippocampus, where it plays a dominant role in regulating the trafficking of AMPA receptors to the postsynaptic membrane and modulating their kinetic properties, such as deactivation and desensitization rates (PubMed: 22421392). Because overactivation of glutamatergic signaling is a hallmark of epilepsy, TARP gamma-8 has emerged as a high-interest therapeutic target for drug-resistant seizures. Selective targeting of gamma-8 allows for regional modulation of AMPA receptors, potentially avoiding the severe side effects like ataxia and sedation associated with non-selective AMPA receptor antagonists like perampanel (PubMed: 27151034). Experimental drugs such as LY3130571 act as negative allosteric modulators that specifically bind the AMPA-TARP gamma-8 complex to reduce excitatory neurotransmission (PubMed: 31086307). This specificity offers a novel approach to treating neurological conditions while preserving normal motor and sensory functions governed by other TARP-AMPA combinations elsewhere in the central nervous system.

Other names

TARP gamma-8Transmembrane AMPA receptor regulatory protein gamma-8Neuronal voltage-gated calcium channel gamma-8 subunit

Negative allosteric modulation of AMPA receptors associated with the gamma-8 subunit