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Receptor crosstalk. Implications for cardiovascular function, disease and therapy
1Cardiovascular Pharmacology Laboratory, Biological and Medical Research Department, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia. dzimiri@kfshr.edu.sa
Insights
Cardiac G protein-coupled receptors regulate heart function through complex signaling pathways. Receptor crosstalk ensures circulatory control in both health and disease.
Area of Science:
- Cardiovascular Physiology
- Molecular Pharmacology
- Cell Signaling
Background:
- Key signaling cascades like beta1-adrenoceptors, renin-angiotensin-aldosterone system, and natriuretic peptides regulate cardiac function.
- Other receptors (alpha1-adrenoceptors, adenosine, endothelin, opioid) are crucial for cardiovascular regulation, especially in disease states.
- Most cardiovascular receptors are G protein-coupled receptors (GPCRs) mediating signals via Gs, Gi, and Gq/11 proteins.
Purpose of the Study:
- To elucidate the intricate signaling networks governing cardiac circulatory function.
- To understand the role of receptor crosstalk in maintaining cardiovascular homeostasis.
- To explore the adaptive mechanisms employed by the heart to compensate for signaling pathway disruptions.
Main Methods:
- Analysis of established signaling cascades (beta1-adrenoceptors, RAAS, natriuretic peptides).
- Investigation of less evident cardiac receptor systems (alpha1-adrenoceptors, adenosine, endothelin, opioid).
- Examination of GPCR coupling to Gs, Gi, and Gq/11 proteins and downstream effectors.
Main Results:
- Identified three primary signaling cascades and several secondary receptor systems crucial for cardiac function.
- Demonstrated that GPCRs utilize Gs, Gi, and Gq/11 proteins to modulate adenylate cyclases and phospholipases.
- Revealed extensive receptor crosstalk involving second messengers and protein kinases, directing signaling pathways.
- Highlighted the heart's intrinsic capacity for harmonizing signaling and activating compensatory mechanisms.
Conclusions:
- Receptor crosstalk is fundamental for maintaining integrated circulatory control of contractile apparatus, blood pressure, and volume.
- These complex signaling interactions are vital for both normal physiological function and adaptation during disease.
- The heart possesses inherent mechanisms to ensure functional integrity despite potential signaling pathway losses.
Abstract:
There are at least three well-defined signalling cascades engaged directly in the physiological regulation of cardiac circulatory function: the beta1-adrenoceptors that control the cardiac contractile apparatus, the renin-angiotensin-aldosterone system involved in regulating blood pressure and the natriuretic peptides contributing at least to the factors determining circulating volume. Apart from these pathways, other cardiac receptor systems, particularly the alpha1-adrenoceptors, adenosine, endothelin and opioid receptors, whose physiological role may not be immediately evident, are also important with respect to regulating cardiovascular function especially in disease. These and the majority of other cardiovascular receptors identified to date belong to the guanine nucleotide binding (G) protein-coupled receptor families that mediate signalling by coupling primarily to three G proteins, the stimulatory (Gs), inhibitory (Gi) and Gq/11 proteins to stimulate the adenylate cyclases and phospholipases, activating a small but diverse subset of effectors and ion channels. These receptor pathways are engaged in crosstalk utilizing second messengers and protein kinases as checkpoints and hubs for diverting, converging, sieving and directing the G protein-mediated messages resulting in different signalling products. Besides, the heart itself is endowed with the means to harmonize these signalling mechanisms and to fend off potentially fatal consequences of functional loss of the essential signalling pathways via compensatory reserve pathways, or by inducing some adaptive mechanisms to be turned on, if and when required. This receptor crosstalk constitutes the underlying basis for sustaining a coherently functional circulatory entity comprising mechanisms controlling the contractile apparatus, blood pressure and circulating volume, both in normal physiology and in disease.