Tài liệu Báo cáo Y học: Receptor crosstalk Implications for cardiovascular function, disease and

REVIEW ARTICLE

Receptor crosstalk

Implications for cardiovascular function, disease and therapy

Nduna Dzimiri

Cardiovascular Pharmacology Laboratory, Biological and Medical Research Department, King Faisal Specialist Hospital &Research

Centre, Riyadh, Saudi Arabia

There are at least three well-defined signalling cascades

engaged directly in the physiological regulation of cardiac

circulatory function: the b1-adrenoceptors that control the

cardiac contractile apparatus,the renin-angiotensin-aldo￾sterone 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 a1-adreno￾ceptors,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 car￾diovascular 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 phospho￾lipases,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 dif￾ferent 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 con￾trolling the contractile apparatus,blood pressure and cir￾culating volume,both in normal physiology and in disease.

Keywords: receptor crosstalk; heart; vasculature; regulatory

systems; subcellular; contractile function; G-proteins; heart

failure; hypertension; hypertrophy; signal transduction.

INTRODUCTION

The cardiovascular circulatory function constitutes a very

sophisticated network of several highly synchronized cir￾cuits to ensure the sustention of human life by maintaining

or increasing blood supply providing oxygen and nutrients

to active tissue,and by redistributing the blood to prevent

heat loss from the body. In humans,multiple cardiovascular

regulatory mechanisms have evolved to uphold this function

at three major levels: contractile apparatus,blood pressure

and circulating volume. Apart from its ability to ensure a

smooth supply of nutrients to various organs,this network

also has the capacity to adapt to minor changes in vascular

resistance that may influence the caliber of arterioles and

other resistance vessels,and thus alter capillary hydrostatic

pressure. Such circulatory adjustments are effected syner￾gistically by local (autoregulatory) as well as systemic

mechanisms in both the heart and peripheral circulatory

organs. The autoregulatory mechanisms are a result of the

intrinsic contractile response of smooth muscle to stretch,in

combination with vasodilatation produced by metabolic

changes leading to a decrease in oxygen tension,pH,and

local vasoconstrictors,such as serotonin. Systemic regula￾tory mechanisms involve vasodilators such as the kinins,

Correspondence to N. Dzimiri,Biological & Medical Research Department (MBC-03),PO Box 3354,Riyadh 11211,Saudi Arabia.

Fax: + 966 1442 7858,Tel.: + 966 1442 7870,E-mail: [email protected]

Abbreviations: A,adenosine receptor subtype; AC,adenylate cyclase; Ach,acetylcholine; ACE,angiotensin converting enzyme; ADO,adenosine

receptors; ANG II,angiotensin II; ANP,atrial natriuretic peptide; ANPR,ANP receptor; AP-1,activating protein; AR,adrenoceptors; ATR,

angiotensin receptor; BNP,brain natriuretic peptide; BNPR,BNP receptor; BP,blood pressure; [Ca2+],calcium channel; [Ca2+]i,intracellular

calcium; [Ca]v,voltage-gated Ca2+ channel; cAMP,3¢,5¢-cyclic adenosine monophosphate; cGMP,3¢,5¢-cyclic guanosine monophosphate;

CNS,central nervous system; CV,cardiovascular; diacylglycerol,diacylglycerol; ET-1,endothelin-1; ETR,endothelin receptor; ETC,endothelial

cells; 5-HT4,5-hydroxytryptamine; ICa,calcium current; IK,inward rectifying K+ current; GC,guanylate cyclase; iNOS,inducible nitric oxide

synthase; InsP3,inositol triphosphate; IPN,isoproterenol; [K+],potassium channel; [K]ATP,ATP-dependent K+ channel; [K+]D,delayed rectified

K+ channel; MAPK,mitogen-activated protein kinase; MR,muscarinic cholinergic receptors; Na,sodium; NE,norepinephrine; NO,nitric oxide;

eNOS,cardiac nitric oxide synthase; OP,opioid receptors; PE,phenylephrine; PIE,positive inotropic effect; PKC,protein kinase C; PLA2,

phospholipase A2; PLC,phospholipase C; PLD,phospholipase D; PKG,cGMP-dependent protein kinase; PPase,phosphoprotein phosphatase;

PP2A,phosphoprotein phosphatase 2A; PTK,protein tyrosine kinase; PTPase,protein tyrosine phosphatase; PTX,Pertussis toxin; RAS,renin￾angiotensin aldosterone system; RPIA, N6

-phenylisopropyladenosine; VECs,vascular endothelial cells; VSM,vascular smooth muscle.

(Received 12 March 2002,revised 29 June 2002,accepted 14 August 2002)

Eur. J. Biochem. 269,4713–4730 (2002) FEBS 2002 doi:10.1046/j.1432-1033.2002.03181.x