Current and future G protein-coupled receptor signaling targets for heart failure therapy

Figures & data

Figure 1 G protein-coupled receptors and their signaling pathways involved in heart failure pathophysiology.

Abbreviations: Aldo, aldosterone; AM, adrenomedullin; AR, adrenoceptor; AT₁R, angiotensin II type 1 receptor; CRFR, corticotrophin-releasing factor receptor; DAG, 2-diacylglycerol; EGFR, epidermal growth factor receptor; Epi, epinephrine; GCGR, glucagon receptor; GLP1R, glucagon-like peptide-1 receptor; GPCRs, G protein-coupled receptors; GRK, GPCR kinase; NE, norepinephrine; PDE, phosphodiesterase; RXFP, relaxin family peptide; SNS, sympathetic nervous system; ???, indicates effect currently under investigation; βarr, beta arrestin; G_s, stimulatory G protein; G_i/G_o, inhibitory/other G protein; Rho, Ras homolog gene family member A; Epac, exchange protein directly activated by cAMP; AC, adenylate cyclase; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C; V1R, vasopressin receptor type 1; RhoK, Rho-dependent kinase.

Table 1 Potential G protein-coupled receptor signaling targets for drug development in heart failure

Target/modality	Representative agents(s)	HF type to be treated	Potential desirable effect(s) in HF	Notes
β2AR stimulation (with concurrent β1AR inhibition)	Clenbuterol	Chronic HF	Cardioprotection ↑ Survival	Compatible with asthma, T2DM, and therapies of other diseases
α2AR agonism/sympatholysis	Clonidine, moxonidine, bucindolol	Chronic HF	Cardioprotection ↑ Survival ↓ Adverse remodeling	α2AR desensitization in chronic HF and incompatibility of excessive sympatholysis with life are potential problems
AT1R-dependent Gq protein signaling antagonism	ARBs (eg, losartan)	Chronic HF	Cardioprotection ↑ Survival ↓ Adverse remodeling ↓ Hypertrophy	↓ SNS tone additional advantage in HF treatment
Gi/o protein stimulation	None known as yet	Chronic HF	Cardioprotection ↑ Survival	↓ contractility, CO (acutely) and bradycardia are disadvantages
Gq protein/PKCβ2 inhibition	GqI, ruboxistaurin, LY379196	Chronic HF	↓ Adverse remodeling ↓ Hypertrophy
Endothelin receptor antagonism	Bosentan, ambrisentan	Right atrial/ventricular HF	Improved pulmonary arterial pressure	↓ PAH ↓ SNS tone (?) potential advantage
AIR (partial) agonism	Capadenoson	Chronic HF	Cardioprotection ↑ Survival	↓ arrhythmias, benefit in ischemic preconditioning are potential advantages; bradycardia is a disadvantage (although is less with partial agonism)
Adrenomedullin receptor agonism	Adrenomedullin, intermedin	Acute and chronic HF	↑ Contractility, CO Improved circulation parameters (BP, natriuresis)	Benefit in chronic HF unknown
Relaxin receptor agonism	Serelaxin (Rxn-2)	ADHF	↑ Contractility, CO Improved circulation parameters (BP, natriuresis)	Serelaxin currently in clinical trials for ADHF (RELAX-AHF)
CRFR2 agonism	Stresscopin, Ucn-1, Ucn-2	ADHF	↑ Contractility, CO Improved circulation parameters (BP, natriuresis, vasodilation)	Benefit in chronic HF unknown
Vasopressin receptor antagonism	Tolvaptan (v2R-selective)	Chronic HF	Improved circulation parameters (BP, natriuresis, diuresis, vasodilation), ↓ Hyponatremia ↓ Cardiac hypertrophy (?)	Direct cardiac effects unknown, Tolvaptan approved in several countries for HF but not in the USA
Glucagon peptide receptor agonism	Glucagon, exenatide (GLP1R peptide agonist)	Chronic HF, diabetic cardiomyopathy	↑ Contractility, CO Cardioprotection ↑ Survival ↑ Myocyte proliferation	Glucagon is used to acutely raise CO in ADHF if patient is on β-blockers, Potential advantage in HF complicated with DM
RhoA/RhoK inhibition	Fasudil (RhoK inhibitor)	Chronic HF	↓ Adverse remodeling after Mi
Epac inhibition	None known as yet	Chronic HF	Cardioprotection (?) ↓ Arrhythmias (?)
GRK2 blockade	Paroxetine, βARKct	Acute and chronic HF	↑ Contractility, CO Cardioprotection ↑ Survival ↓ Cardiac hypertrophy ↓ SNS (and RAAS) tones	βARKct is entering clinical trials for chronic HF soon
βarr2 stimulation (with concurrent βarr1 inhibition)	None known as yet, βarr1ct	Acute and chronic HF	↑ Contractility, CO Cardioprotection ↑ Survival ↓ SNS (and RAAS) tones	Exact role(s) of βarr1 versus βarr2 in the heart still await delineation, TRV027 (AT1R βarr-biased agonist peptide) currently in development for ADHF

Abbreviations: A1R, adenosine type 1 receptor; ADHF, acute decompensated HF; AR, adrenoceptor; ARB, angiotensin receptor blocker; AT₁R, angiotensin ii type 1 receptors; BP, blood pressure; cAMP, cyclic adenosine monophosphate; CO, cardiac output; CRFR2, corticotrophin-releasing factor receptor type 2; DM, diabetes mellitus; Epac, exchange protein directly activated by cAMP; GPCR, G protein-coupled receptor; G_qI, G_q protein inhibitor peptide; GRK, GPCR kinase; HF, heart failure; MI, myocardial infarction; PAH, pulmonary arterial hypertension; PKC, protein kinase C; RAAS, renin–angiotensin–aldosterone system; RELAX-AHF, Relaxin in Acute Heart Failure clinical trial; RhoA/K, ras homolog gene family member A/Rho-dependent kinase; Rxn-2, relaxin-2; SNS, sympathetic nervous system; T2DM, type 2 diabetes mellitus; Ucn, urocortin; V₂R, vasopressin receptor type 2; βarr, beta arrestin; ?, indicates effect currently under investigation; ct, C-terminal fragment; G_i/G_o, inhibitory/other G protein; GLP1R, glucagon-like peptide-1 receptor; βARK, beta-adrenergic receptor kinase.