The insulin receptor family in the heart: new light on old insights

Figures

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  Figure 1. Insulin receptor family signalling (A) Insulin receptors (INSRs, black) and the related receptor family members, IGF1 receptors (IGF1Rs, blue) and insulin receptor-related receptors (INSRRs, yellow) are expressed at the cell surface as preformed heterotetramers, each comprising two hemi-receptors composed of one α- and one β-subunit. Each α- and β-subunit and the two α-subunits are cross-linked by disulphide bridges. The extracellular α subunits bind insulin or IGFs as indicated or are responsive to alkaline pHo. The β-subunits have a tyrosine kinase domain (red). Alternative splicing generates two isoforms of INSR, INSR-A and INSR-B, without or with (respectively) exon 11 (pink). Hybrid receptors can form between the family members. IGF2 also binds to the cation-independent mannose 6-phosphate receptor (CI-M6PR) that directs IGF2 and other molecules to the lysosome for degradation. (B) Insulin or IGFs bind to INSRs/IGF1Rs causing receptor phosphorylation and full activation of the tyrosine kinase, with additional phosphorylation of tyrosine residues (pY) on the β-subunit. These recruit adapter proteins including insulin receptor substrates (IRS) that become phosphorylated. IRS…

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  Figure 2. Glucose metabolism through the glycolytic and pentose phosphate pathways: regulation by PKB/Akt PKB/Akt phosphorylates RabGAPs (AS160/Tbc1d4, Tbc1d1) to prevent their inhibitory action (red type), increasing translocation of vesicles containing the glucose transporter GLUT4 to the membrane (blue arrow). This increases glucose uptake into the cell. Hexokinase II (HKII) converts glucose to glucose 6-phosphate (G6P). It is tethered to the mitochondrial membrane, interacting with the voltage-dependent anion channel (VDAC), allowing it to access ATP directly from the mitochondria, and facilitating direct transfer of ADP back into the mitochondria. HKII expression and activity is increased by PKB/Akt signalling (blue type) increasing production of G6P. Glycolysis (centre). G6P is converted to fructose 6-phosphate which is then converted to fructose 1,6-bisphosphate by phosphofructokinase (PFK) in the rate-limiting step of the pathway. Fructose 6-phosphate interconversion with fructose 2,6-bisphosphate is performed by the cardiac isoform of phosphofructokinase 2 (PFKB2), an enzyme with dual kinase (K) and phosphatase (P) activity. PKB/Akt phosphorylates and inhibits the phosphatase…

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  Figure 3. Cross-talk from α1-adrenergic receptors (α1-ARs) to INSR/INSRR receptors in the heart: possible mechanisms (i) α1-ARs are G-protein-coupled receptors that couple through Gαq to activate phospholipase C (PLC) β and possibly PLCε. PLCβ/ε hydrolyses phosphatidylinositol 4,5 bisphosphate (PIP2) to produce diacylglycerol (DAG) which activates protein kinase C (PKC) family members and guanine nucleotide exchange factors for Ras (e.g. RasGRP). This results in activation of the ERK1/2 cascade that affects downstream signalling and gene expression. (ii) Activation of the small G protein Rac1 results in an increase in production of reactive oxygen species (ROS) via NADPH oxidases (NOX). ROS inhibit protein tyrosine phosphatases (PTPs), and this may lead to increased tyrosine phosphorylation of INSRs/INSRRs, with receptor activation and downstream signalling. (iii) Src family kinases (SFKs) may be activated, possibly by phosphatidic acid produced by phospholipase D (activated by PKC; pathway not shown). SFKs may phosphorylate INSRs/INSRRs directly to cause receptor activation. (iv) α1-ARs increase intracellular pHi via an unknown mechanism and this needs to be neutralised. SFKs…

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  Figure 4. Possible mechanisms of cardioprotection resulting from stimulation of insulin receptor family members Activation of insulin receptor family members results in activation of protein kinase B (PKB, also known as Akt). (i) PKB/Akt signalling influences cell death by reducing mitochondrial-dependent apoptosis, increasing hexokinase II (HKII) and inhibiting glycogen synthase kinase 3 (GSK3) activities. This prevents opening of the mitochondrial permeability transition pore (mPTP). Inhibition of FoxO transcription factors reduces expression of pro-apoptotic proteins. Signalling via mTORC1 inhibits autophagy via Ulk1. Activation of eNOS may reduce cell death, acting to promote vasodilation and, thus, reduce workload. It also reduces vascular inflammation. Phosphorylation of cGAS and STING inhibits interferon production. Increased flux through the pentose phosphate pathway (PPP) increases antioxidant capacity in the cell by increasing production of NADPH and glutathione (GSH). (ii) PKB/Akt increases metabolism, providing the cell with options for reducing oxygen needs whilst sustaining energy production, and maintaining antioxidant capability via the NADPH/glutathione system. Glucose…