Molecular interplay between glycogen synthase kinase 3 beta and A-kinase anchoring protein 11 in bipolar disorder: a narrative review.

Bipolar disorder (BD) is a complicated psychiatric condition which is determined by episodic mood instability, yet its underlying biological foundation still remains poorly understood. A-kinase anchoring protein 11(AKAP11) has been identified a high-confidence risk gene through recent large scale genomic investigations, its ultra-rare protein truncating variants lead to seven fold increased risk for BD and Schizophrenia. This narrative review aims to examine the molecular interplay between AKAP11, a multivalent scaffolding protein, and Glycogen synthase kinase-3β (GSK3β), a crucial regulator of synaptic plasticity and the primarily suspected target of lithium therapy. AKAP11 acts as a structural chassis, which sequesters GSK3β amongst discrete subcellular microdomains to facilitate its localised suppression by PKA-mediated phosphorylation. We focus how this protein-protein interface is selectively disrupted by "edgetic" mutations, which leads to escape of GSK3β from homeostatic control through spatial mislocalization. The resultant cellular abnormalities consist of impaired dendritic spine stability, proteostatic stress caused by defective autophagy of signalling complexes, and reduced synaptic transmission. Changes in excitatory and inhibitory balance and signalling stability, that are linked to bipolar disorder, may be facilitated by these pathways. However, there are limited evidences stating that direct disruption of AKAP11-GSK3β interaction may lead to episodic-mood state transition. Therefore, even though the clinical significance of AKAP11 and GSK3β interaction is yet to be established, its further investigation is a potential therapeutic target.