Mutations in DISC1 alter IP3R and voltage-gated Ca2+ channel functioning, implications for major mental illness.

Abstract

Disrupted in Schizophrenia 1 (DISC1) participates in a wide variety of developmental processes of central neurons. It also serves critical roles that underlie cognitive functioning in adult central neurons. Here we summarize DISC1's general properties and discuss its use as a model system for understanding major mental illnesses (MMIs). We then discuss the cellular actions of DISC1 that involve or regulate Ca²⁺ signaling in adult central neurons. In particular, we focus on the tethering role DISC1 plays in transporting RNA particles containing Ca²⁺ channel subunit RNAs, including IP3R1, CACNA1C and CACNA2D1, and in transporting mitochondria into dendritic and axonal processes. We also review DISC1's role in modulating IP₃R1 activity within mitochondria-associated ER membrane (MAM). Finally, we discuss DISC1-glycogen synthase kinase 3β (GSK3β) signaling that regulates functional expression of voltage-gated Ca²⁺ channels (VGCCs) at central synapses. In each case, DISC1 regulates the movement of molecules that impact Ca²⁺ signaling in neurons.