Figure 3.

InsP₃-mediated signalling in regulation of gene expression and mitochondrial function. (a) Nuclear and cytosolic Ca²⁺ increases generated by Ca²⁺ release from InsP₃Rs regulate gene expression underlying cardiomyocyte hypertrophic remodelling. Ca²⁺ released from InsP₃Rs binds to calmodulin (CaM), which then activates CaM-dependent kinase II (CaMKII) and calcineurin (CaN). Activated CaMKII phosphorylates the inhibitory factor histone deacetylase (HDAC) and induces its export from the nucleus, resulting in MEF2 de-repression and induction of hypertrophic gene expression. Meanwhile, CaN dephosphorylates the nuclear factor of activated T-cells (NFAT) promoting its nuclear translocation and hypertrophic gene transcription. Ang II, angiotensin II; CaM, calmodulin; CaMKII, Ca²⁺/calmodulin-dependent protein kinase II; Ca_v1.2, α1C, subunit of voltage-gated L-type calcium channel; CaN - calcineurin; ET-1, endothelin-1; HDAC, histone deacetylase; IGF1R, insulin-like growth factor 1 receptor; IP₃, inositol 1,4,5-trisphosphate; IP₃R2, inositol trisphosphate receptor type 2; MEF2, myocyte enhancer factor-2; NFAT, nuclear factor of activated T cells, RyR2, ryanodine receptor type 2. (b) Mitochondrial Ca²⁺ uptake sites are closely localized to Ca²⁺ release sites at the junctional SR forming ‘hotspots’ with the help of tethers MFN and FUNDC1. Ca²⁺ released from the SR via RyRs is taken up via the voltage-gated anion channel (VDAC) associated with the mitochondrial Ca²⁺ uniporter (MCU) (1). In mitochondria, Ca²⁺ controls ATP production and apoptosis. Ca²⁺ is extruded from the mitochondria through Na⁺/Li⁺/Ca²⁺ exchanger (NCXL) and Ca²⁺/H⁺ exchanger (mHCX). Upon stimulation of Gα_q by ET-1, Ang II or NE, InsP₃ activates Ca²⁺ release from the SR leading to its uptake into the mitochondrial matrix through either VDAC (2) or mRyR1 (4). While Ca²⁺ transfer via VDAC1—GRP75—InsP₃R results in induction of cell apoptosis (2), when taken up through mRyR1 it is associated with increased ATP production (4). To counterbalance InsP₃-mediated mitochondrial Ca²⁺ overload during cellular stress, NOX4 augments the level of active phosphorylated AKT, which in turn phosphorylates and suppresses InsP₃Rs thereby inhibiting Ca²⁺ flux from the SR to mitochondria (3). Akt, protein kinase B; Ang II, angiotensin II; ET-1, endothelin-1; FUNDC1, FUN14 domain-containing protein 1; GRP75, chaperone 75 kDa glucose-regulated protein; MCU, mitochondrial Ca²⁺ uniporter; MFN, mitofusin; mHCX, mitochondrial Ca²⁺/H⁺ exchanger; NCXL, Na⁺/Li⁺/Ca²⁺ exchanger; NE, norepinephrine; NOX4, NADPH oxidase 4; VDAC, voltage-gated anion channel. (Online version in colour.)