Potential for therapeutic targeting of AKAP signaling complexes in nervous system disorders

Abstract

A common feature of neurological and neuropsychiatric disorders is a breakdown in the integrity of intracellular signal transduction pathways. Dysregulation of ion channels and receptors in the cell membrane and the enzymatic mediators that link them to intracellular effectors can lead to synaptic dysfunction and neuronal death. However, therapeutic targeting of these ubiquitous signaling elements can lead to off-target side effects due to their widespread expression in multiple systems of the body. A-kinase anchoring proteins (AKAPs) are multivalent scaffolding proteins that compartmentalize a diverse range of receptor and effector proteins to streamline signaling within nanodomain signalosomes. A number of essential neurological processes are known to critically depend on AKAP-directed signaling and an understanding of the role AKAPs play in nervous system disorders has emerged in recent years. Selective targeting of AKAP protein-protein interactions may be a means to uncouple pathologically active signaling pathways in neurological disorders with a greater degree of specificity. In this review we will discuss the role of AKAPs in both regulating normal nervous system function and dysfunction associated with disease, and the potential for therapeutic targeting of AKAP signaling complexes.

Keywords: AKAP; Calcium; Ion channel; Nervous system; PKA; cAMP.