Biology Reference
In-Depth Information
tissues, and organs of the cardiovascular system in which barr effects are exerted; for
example, cardiac myocyte or fibroblast, vascular smooth muscle, adrenal gland and
platelet.
In the broader scope of cardiovascular barr pharmacology, a discussion of
the barr
“
bias
”
of certain cardiovascular GPCR ligands is also included.
1. INTRODUCTION
Of the four mammalian arrestin isoforms known, only the two ubiq-
uitous (outside the retinal system)
b
arrestins [i.e.,
b
arrestin1 and -2 (
b
arr1
and -2) or Arrestin2 and -3 (Arr2 and -3)] are expressed in the cardiovascular
system. Several of the seven transmembrane-spanning receptors (7TMRs)
or G-protein-coupled receptors (GPCRs) that these two
b
arrs regulate play
enormously important roles in cardiovascular physiology and homeostasis.
For instance, cardiac function (contractility) is tightly controlled by the
activity of
b
-adrenergic receptors (
b
1
- and
b
2
ARs) located in the mem-
branes of cardiac myocytes. Cardiac structure and morphology are regulated
by angiotensin II (AngII) type 1 receptors (AT
1
Rs) present (mainly) in car-
diac fibroblast and endothelial cell membranes, and also, to a lesser extent, in
cardiomyocyte membranes. Heart rate is modulated by the balance between
the activities of
b
-adrenergic and muscarinic cholinergic receptors located in
various anatomical segments of the cardiac electrical conduction system.
Vascular tone is regulated by
a
- and
b
-adrenergic, endothelin (ET), AngII,
and bradykinin receptor activation; renal function is fine-tuned by AngII,
adrenergic, vasopressin, and dopaminergic receptors; and systemic blood
pressure is regulated by changes in all these parameters of cardiovascular
function (i.e., heart rate, vascular resistance, and fluid/electrolyte balance).
Each of these processes is kept in balance, to a large degree, by GPCRs. Fur-
thermore, even the neurohormonal control of the circulatory system,
whether it be catecholamine and corticosteroid release by the adrenal glands,
activation of the renin-angiotensin-aldosterone system by the
juxtaglomerular apparatus of the kidneys, or release of neurotransmitters
by central and peripheral neurons innervating cardiovascular organs, is under
tight regulation by various GPCRs.
Given that signaling from cardiovascular 7TMRs constitutes such an
integral part of cardiovascular function, and that
b
arrs, both of which are
expressed throughout the cardiovascular system, interact with and tightly
regulate this signaling, it should come as no surprise that the roles
b
arrs
play in cardiovascular biology, physiology, and pathology are both
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