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

Ann R Rittenhouse; Sonia Ortiz-Miranda; Agata Jurczyk

doi:10.1042/NS20180122

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

Neuronal Signal. 2021 Dec 7;5(4):NS20180122. doi: 10.1042/NS20180122. eCollection 2021 Dec.

Authors

Ann R Rittenhouse¹, Sonia Ortiz-Miranda¹, Agata Jurczyk²

Affiliations

¹ Program in Neuroscience, NeuroNexus Institute, Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01605, U.S.A.
² Agata Jurczyk, Black Diamond Therapeutics, One Main Street, 10th Floor, Cambridge, MA 02142, U.S.A.

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.

Keywords: AMPKalpha; Ca2+ signaling; CaValpha1 subunits; GSK3beta; SNARE proteins; exocytosis.

Publication types

Review