Inositol 1,4,5-trisphosphate receptors in cardiomyocyte physiology and disease

Figure 1.. InsP3R expression in the heart. (a) InsP3 is generated by activated phospholipase C (PLC) following the engagement of G-protein coupled receptors (GPCRs) liganded by either angiotensin II (Ang II; angiotensin receptor, AT1), endothelin-1 (ET-1; endothelin receptor, ET receptors), adenosine triphosphate (ATP; purinergic receptors, P2Y), the catecholamines (CA; α and β-adrenoreceptors, α-AR and β-AR) epinephrine (Epi) and norepinephrine (NE) and insulin-like growth factor 1 (IGF-1; IGF-1 receptor, IGF-1R). After diffusion into the cytosol or the nucleus, InsP3 binds to each subunit within the InsP3R tetramer leading to channel opening and release of Ca2+ from intracellular Ca2+ storage sites. (b) InsP3R2 localization relative to RyR2 (top) and t-tubules (bottom). InsP3Rs are stained in green, RyRs are stained in purple and the t-tubules (Caveolin (Cav3)/NCX) are in grey. A 4× zoom of the white square is shown. (c) Log normalized expression of the genes encoding the three inositol 1,4,5-trisphosphate receptors (ITPR1-3) and the gene encoding the type 2 RyR (RYR2) in the cardiomyocyte single nucleus RNA-Seq from each of the four heart chambers. (d) (i) Uniform Manifold Approximation…

Figure 2.. Mechanisms of InsP3-mediated regulation of ECC in atrial and ventricular cardiomyocytes. Atria: GPCRs activated by ET-1 or Ang II produce InsP3 that stimulates Ca2+ release via InsP3 receptors type 1 or 2 (InsP3R1/2). This InsP3 mediated Ca2+ release in turn acts either via priming of proximal RyRs for Ca2+ release or via activation of Ca2+-sensitive adenylyl cyclases (AC1 or AC8) and activation of PKA by cAMP, which then phosphorylates RyRs, modulates Ca2+ transients and hence strength of contraction. Ventricle: Ca2+ release via InsP3Rs facilitates RyR opening and enhances their recruitment during ECC (1). However, the enhanced activity of RyRs leads also to enhanced SR Ca2+ leak (2), which reduces the Ca2+ load in the SR and can lead to activation of NCX. If the SR Ca2+ leak is of sufficient amplitude, via NCX, it can trigger substantial Na+ influx into the cell leading to membrane depolarization manifest as a delayed after-depolarisation (DAD) and potentially AP generation (3). AC, adenylyl cyclase; Ang II, angiotensin II; ATP, adenosine-5′-triphosphate; cAMP, cyclic adenosine monophosphate, Cav1.2, α1C, subunit of voltage-gated L-type calcium channel; DAD, delayed…

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; Cav1.2, 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)…