Primary G protein Tissue distribution Primary effector in heart tissue


Gs Gs/Gi Heart

Adenylyl cyclase,

L-type calcium channel cAMP/PKA


Vessels, heart, lung, kidney Adenylyl cyclase,

L-type calcium channel cAMP/PKA, MAPK

Adipose, heart Adenylyl cyclase cAMP/PKA

cAMP, cyclic adenosine 3',5'-monophosphate; Gi, inhibitory G protein; Gs, stimulatory G protein; MAPK, mitogen-activated protein kinase; PKA, protein kinase A.

been made to classify them according to different subtypes. For example, common a-subunits include: (1) as (stimulatory), which activates adenyl cyclase (AC); (2) ^(inhibitory), which inhibits AC; (3) a0, which modulates calcium channels and phospholipase C; and (4) az, which activates phospholipase C. In general, each a-subunit contains a region that interacts with the receptor, a site that binds GTP (guanosine triphosphate), and a site that interacts with the effector system.

3.4. Receptor Function and Regulation

The traditional concepts of G protein-coupled receptor function are best illustrated in Fig. 1. First, an agonist binds to a receptor molecule, and then the seven-transmembrane-span-ning receptor molecule interacts with a specific G protein; this in turn modulates a specific effector. Examples of typical agonists, receptors, G proteins, and effectors are provided in Fig. 1. Although this illustration provides a general summary of the individual components needed for proper G protein-coupled receptor function, a more thorough understanding of the G protein receptor-mediated signaling, as well as its regulation, is best accomplished by the more specific example of the well-characterized p-AR system. Therefore, the discussion starts with the physiologically, pathophysiologically, and clinically highly relevant seven-transmembrane-spanning p-AR.


4.1. Classification of ^-Adrenergic Receptors

Table 2 summarizes the general features of p-AR subtypes identified to date (1); note that there are three subtypes. Although all of the subtypes can be found in the heart, the predominant subtype in the vasculature is the p2-AR. Importantly, norepineph-rine and epinephrine are the endogenous agonists (catechola-mines) that bind specifically to all three p-AR subtypes.

Pharmacologically, p1- and p2-receptors are characterized by an equal affinity for the exogenous full agonist isoproterenol and epinephrine; norepinephrine (the neurotransmitter of the sympathetic nervous system) has a 10- to 30-fold greater affinity for the p1-AR subtype. Also, p1-ARs are more closely located to synaptic nerve termini than p2-ARs and are therefore exposed and activated by higher concentrations of released norepinephrine.

4.2. ^-Adrenergic Activation and Cardiovascular Function p-ARs are probably one of the most important (and most widely studied) types of cardiac receptor systems. Activation of p-ARs regulates important cardiovascular functions and is integral to the body's "flight-and-fight" response. For example, during exercise, heart rate and contractility both increase, cardiac conduction accelerates, and cardiac relaxation (which is an active process requiring adenosine triphosphate [ATP]) is enhanced. Moreover, vascular relaxation (vasodilation) of many vascular beds can be observed during exercise (e.g., in skeletal muscles).

All these effects are at least partially a direct consequence of p-AR activation and involve key elements of G protein receptor signaling: (1) receptor binding, (2) G protein activation, and

(3) activation of an effector system. Importantly, most of these specific physiological cardiac effects are mediated via activation of p1-AR; the vascular effects are mediated through the p2-receptor subtype. However, heart muscle also contains p2-receptors (as well as p3-receptors). Nevertheless, the p1-recep-tor subtype is the predominant cardiac isoform in healthy humans. More specifically, although there is a substantial population of p2-receptors in the atria, only around 20-30% of the total p-AR population are p2-ARs in the left ventricle (2).

Not only is the activation of p-ARs and their associated signaling transduction key in understanding the physiology of the cardiovascular system, but also it has been recognized over the past decades that p-AR activations also play key roles in cardiac disease processes such as heart failure (3). For example, an apparent paradox exists, namely, that p-adrenergic blockers (preceptor antagonists) are beneficial in patients with heart failure; this is discussed in more detail next.

4.2.1. Effects of p-Receptor Activation on the Heart p-Receptor activation on the heart regulates cardiac function on a beat-to-beat basis. Specifically, p-AR stimulation causes increases in heart rates (positive chronotropic effect), increases in contractility (positive inotropic effect), enhancements in cardiac relaxation (positive lusitropic effect), and/or increases in conduction velocities (positive dromotropic effect). The molecular mechanisms leading to each of these specific effects are discussed. For further details, refer to the textbook by Opie

(4). Other important effects on cardiac myocytes that should be noted include those caused by enhanced metabolism.

4.2.2. Positive Chronotropic Effect

When activated, p-ARs located on the cells that make up the sinoatrial node increase the firing rate of the sinoatrial node. Although the mechanisms of these effects are not fully understood, they are known to involve activation of G proteins and

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