Atypical GABA Receptors in Pain Circuits
Inhibitory GABAA receptors in the central nervous system are usually composed of two alpha, two beta, and one gamma subunits. These subunits are heterogeneous: there are six different alpha subtypes, three beta subtypes, and three gamma subtypes. The composition of GABAA receptors is important clinically because the subunits can be distinctly targeted by treatments for different disease symptoms. Benzodiazepines (BDZs) target GABAA receptors, strengthening their signaling. Alpha subunits and gamma subunits together contribute to BDZ binding on GABAA receptors, but gamma subunits have received less research attention. Neumann and colleagues address this oversight. They identified a unique GABAA receptor in the spinal dorsal horn, a key site for pain processing. Using mice, the authors found that gamma 1-containing GABAA receptors were highly expressed in this region. Furthermore, they sufficiently supported synaptic clustering of GABAA receptors and BDZ action when gamma 2-containing GABAA receptors in the spinal cord were ablated. These findings suggest that gamma 1-containing GABAA receptors contribute to functionally relevant pain processing circuits. This is a major preclinical advancement and may inform treatment development for pain.
