Acute Contractile Effects of Glucagon-like-Peptide-1 Receptor Agonists in the Human Heart

Figures

• 

  Figure 3. GLP-1R agonists or related drugs I (cf. Table 3). The drugs of interest are peptides or small organic molecules. The drugs stimulate the glucagon-like-protein-1 receptor (GLP-1R), the glucagon receptor (GCGR) or the glucose-dependent insulinotropic polypeptide (GIPR). Thus, danuglipron, lotiglipron and orforglipron are solely agonists of GLP-1R. The same holds true for the naturally occurring exenatide and its more stable derivative lixisenatide. Liraglutide, semaglutide and ecnoglutide closely resemble in their sequence the endogenous GLP-1. Likewise, dulaglutide and albiglutide are agonists of GLP-1R. Mazdutide, survodutide and cotadutide are agonists of both GLP-1R and GCGR. Tirzepatide and brenipatide are dual agonists of GCGR and GIPR. Retatrutide is a triple agonist of GLP-1R, GCGR and GIPR. Dapiglutide is a dual agonist of GLP-1R and the glucagon-like-protein-2 receptor (GLP-2R).

• 

  Figure 1. Schematic action of selective or non-selective GLP-1R agonists. Glucagon, GLP-1 and GIP can activate the glucagon receptor (GCGR), the glucagon-like-protein 1 receptor (GLP-1R) and the glucose-dependent insulinotropic polypeptide (GIPR) in cardiomyocytes, respectively. Then, the stimulatory GTP-binding protein (Gs) can activate adenylyl cyclase (AC) and thereafter cAMP is formed. This cAMP activates the cAMP-dependent protein kinase (PKA). This PKA phosphorylates and activates phospholamban (PLB) and the ryanodine receptor (RYR), both located in the sarcoplasmic reticulum, as well as the inhibitory subunit of troponin (TnI) in the myofilaments, the L-type calcium ion channels (LTCC) in the sarcolemma and the cAMP-responsive-element-binding protein (CREB) in the nucleus. PKA can also phosphorylate phosphorylase kinase, which phosphorylates and activates phosphorylase and this leads to cleavage of glycogen. GCGR, GLP-1R and GIPR can probably also activate phospholipase C (PLC). PLC then forms inositoltrisphosphate (IP3) which can release Ca2+ from in the sarcoplasmic reticulum. Phospholamban in its unphophorylated form inhibits the activity of the sarcoplasmic reticulum Ca2+ ATPase…

• 

  Figure 2. Signal transduction in HAP. Proglucagon is proteolyzed to GLP-1(1-36). GLP-1(1-36) can be truncated to the active metabolite GLP-1(7-36). GLP-1(1-36) and much more potently GLP-1(7-36) can activate the glucagon-like-protein 1 receptor (GLP-1R). Then, at least three different signal pathways can be used: the stimulatory GTP-binding protein (Gs) can activate adenylyl cyclase (AC) and thereafter cAMP is formed. As also seen in Figure 1, this cAMP activates the cAMP-dependent protein kinase (PKA). This PKA phosphorylates and activates phospholamban (PLB) and the ryanodine receptor (RYR), both located in the sarcoplasmic reticulum and cAMP-responsive-element-binding protein (CREB) in the nucleus. In addition, cAMP can activate the Epac2. GLP-1R can also activate phospholipase C (PLC). PLC then forms inositoltrisphosphate (IP3) which can release Ca2+ from internal stores. In addition, PLC may activate protein kinase C (PKC) which may open L-type calcium ion channels (LTCCs) via transient receptor potential channel member 4 (TRPM4) and TRPM5. Then increased Ca2+ can act on the myofilaments to raise force of contraction. GLP-1R can also use a non-canonical pathway to activate β-arrestin…