Guanylatecyclaselinked Receptors

10.1. Soluble Guanylyl Cyclase (Receptor for Nitric Oxide)

Although structurally different, the general principles of receptor signaling as discussed for p-AR apply also for nitric oxide/guanylyl cyclase (GC) signaling. Specifically, the agonist (nitric oxide) is a universal signaling molecule present in all tissues, and its role is important not only in normal physiology, but also in disease. Physiologically, nitric oxide is produced by several isoforms of the enzyme nitric oxide synthase (NOS). Three isoforms have been described to function within the cardiovascular system: eNOS, iNOS, and nNOS.

Nitric oxide is a small, lipid-soluble gas molecule that readily crosses cell membranes. Inside the cell, it typically binds to a receptor, the soluble (cytoplasmatic) GC (an enzyme that converts GTP to cyclic 3',5'-GMP). cGMP is the second messenger and, in the cardiovascularsystem, can activate two major effector systems: cGMP-regulated phosphodiesterases and cGMP-dependent protein kinases (cGKs).

In the vascular smooth muscle cells, nitric oxide inhibits vascular smooth muscle constriction (causes vasodilation) via inhibition of cytoplasmic calcium release. However, the underlying mechanisms for the important vasodilatory effect of nitric oxide are complicated and involve a cGMP-dependent protein kinase (cGKI); these pathways have been reviewed in detail elsewhere (32). Nitric oxide has also been shown to reduce vascular smooth muscle proliferation (clinically important in in-stent restenosis) and migration. It is well established that nitric oxide release may reduce platelet adhesion and activation, as well as vascular inflammation (33). Importantly, nitric oxide insufficiency is considered an important factor in endothelial dysfunction, leading to the increased susceptibility for arterial thrombosis formation (34).

The relevance of nitric oxide signaling is not limited to vascular biology or pathobiology; it has been demonstrated that nitric oxide has an important pathophysiological role in heart failure as well—in the modulation of cardiac function, cardiovascular protection, or in the regulation of apoptosis (35-37).

10.2. Membrane Guanylyl Cyclase A

(Receptors for Natriuretic Peptides)

To date, at least seven membrane-bound enzymes synthesizing cGMP have been identified. All seven of these membrane GCs have a common structure (Fig. 5). For the purpose of this discussion, guanylyl cyclase A (GC-A) has the greatest importance relative to the heart and thus is discussed in detail.

Fig. 5. Basic topology of membrane guanylyl cyclase A receptor. The membrane guanylyl cyclase forms homodimers or higher order structures. cGMP, cyclic guanosine monophosphate; GTP, guanosine triphosphate. Modified from ref. 38. © 2003 Lippincott, Williams, and Wilkins.

10.3. Physiology

Currently, three NPs have been identified: ANP, BNP, and CNP. Both ANP and BNP bind to GC-A and are released in the heart; they are considered cardiac hormones. In general, CNP is mainly produced by the vascular endothelium and may be a regulator of vascular tone and cell growth through guanylyl cyclase B activation.

The receptor consists of an extracellular domain, a kinase homology domain, an a-helical amphipathic region (hinge region), and a C-terminal GC (catalytic) domain (Fig. 5). This receptor is considered to exist in dimers.

The major effects of GC-A are via the formation of and the activation by cGMP. In general, because the agonists are circulating hormones (peptides), a variety of organ systems can be affected simultaneously following ANP/BNP release. ANP is mainly produced in the atrium, and BNP is produced primarily in the ventricles. The primary triggering factors for ANP/BNP release are wall stretch or pressure increases, but they may also involve neurohumoral factors (glucocorticoids, catechola-mines, angiotensin II, and so forth). The main effect of ANP/ BNP release is modulation of blood pressure/volume. The half-lives of ANP/BNP are around 2-5 min.

Interestingly, although both ANP and BNP bind to the same receptors, it has been shown that targeted genetic disruption of ANP or BNP in mice induces a unique phenotype; ANP-deficient mice show arterial hypertension, hypertrophy, and cardiac death, and the BNP-deficient mice phenotype is characterized mostly by cardiac fibrosis. More specifically, BNP has a lower affinity to GC-A than ANP and may act mostly as a local paracrine (antifibrotic) factor. Also, under physiological conditions, the ANP levels are much higher than BNP levels in the circulating blood, and the potency for induced vasorelaxation is also less for BNP compared to ANP (38).

The cardiovascular effects of ANP-GC-A are complex, but can be summarized as hypovolemic and hypotensive, effects that are induced via hormonal, renal, vascular, central nervous system, and other mechanisms. The mostimportant hypoten-sive effects also involve decreased sympathetic activity and complex renal responses, which subsequently lead to increased diuresis (38).

10.4. Role in Cardiac Disease

During chronic hemodynamic overload, ANP and, to an even greater level, BNP expression in the cardiac ventricles is significantly increased. This response may not only maintain both arterial blood pressure and volume homeostasis, but also locally prevent hypertrophy (ANP) and fibrosis (BNP) factors. Although ANP/BNP levels are increased in patients with cardiac hypertrophy or heart failure, the GC-A-mediated effects of these peptides are diminished.

Mechanisms for these responses may be postreceptor defects such as dephosphorylation of GC-A, sequestration of NP by a clearance receptor, altered transcriptional regulation at the gene level, or others (31). However, the processes regulating GC-A activity (and desensitization) are largely unknown. Yet, synthetic BNP (nesiritide) and ANP (anaritide) have been shown to be highly beneficial in the acute treatment of heart failure. Hence, it is conceivable that the thorough understanding of the mechanisms for chronic desensitization, as well as regulation of GC-A receptor signaling, might be important for the development of novel therapeutic approaches for various forms of cardiac disease.

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