Review Article

Adenylyl cyclases: structure, regulation and function in an enzyme superfamily

Under normal circumstances, the heart's rate and force of contraction is tightly regulated to meet the circulatory demands of the body. The sympathetic and parasympathetic nervous systems are primary regulators of cardiac output but a number of integrated systems of the body including the renal system, adrenal glands, vascular endothelium, immune system, and cardiac tissue itself play important roles in regulating circulation and hydroelectrolytic homeostasis. This chapter describes the cellular and molecular basis of myocardial excitation–contraction coupling, explains how the autonomic nervous system regulates excitation–contraction coupling, and examines emerging information on the mechanisms of arrhythmias and the new pharmacologic approaches being taken to treat arrhythmias and chronic heart failure. Much of the organizational structure and some informational content of the first edition of this chapter, written by Sheu and Colecraft (1997), has been retained; however, significant revisions and additions have been made to include dramatic advancements in understanding the molecular biology of ion channels, the autonomic receptor signaling pathways, and the genetic basis of some forms of arrhythmias.

The human placenta plays a central role in pregnancy, and the syncytiotrophoblast cells are the main components of the placenta that support the relationship between the mother and fetus, in apart through the production of progesterone. In this review, the metabolic processes performed by syncytiotrophoblast mitochondria associated with placental steroidogenesis are described. The metabolism of cholesterol, specifically how this steroid hormone precursor reaches the mitochondria, and its transformation into progesterone are reviewed. The role of nucleotides in steroidogenesis, as well as the mechanisms associated with signal transduction through protein phosphorylation and dephosphorylation of proteins is discussed. Finally, topics that require further research are identified, including the need for new techniques to study the syncytiotrophoblast in situ using non-invasive methods.

The published papers on the effects of increased cardiac expression of adenylyl cyclase type 6 (AC6) are reviewed. These include the effects of AC on normal and failing left ventricle in several pathophysiological models in mice and pigs. In addition, the effects of increased expression of AC6 in cultured neonatal and adult rat cardiac myocytes are discussed in the context of attempting to establish mechanisms for the unanticipated beneficial effects of AC6 on the failing heart. This article is part of a Special Section entitled “Special Section: Cardiovascular Gene Therapy”.

Under normal circumstances, the heart’s rate and force of contraction is tightly regulated to meet the circulatory demands of the body. The sympathetic and parasympathetic nervous systems are primary regulators of cardiac output but a number of integrated systems of the body including the renal system, adrenal glands, vascular endothelium, immune system, and cardiac tissue itself play important roles in regulating circulation and hydroelectrolytic homeostasis. This chapter describes the cellular and molecular basis of myocardial excitation–contraction coupling, explains how the autonomic nervous system regulates excitation–contraction coupling, and examines emerging information on the mechanisms of arrhythmias and the new pharmacologic approaches being taken to treat arrhythmias and chronic heart failure. Much of the organizational structure and some informational content of the first edition of this chapter, written by Sheu and Colecraft (1997), has been retained; however, significant revisions and additions have been made to include dramatic advancements in understanding the molecular biology of ion channels, the autonomic receptor signaling pathways, and the genetic basis of some forms of arrhythmias.

The intestinal epithelium is dynamic, with proliferation of undifferentiated crypt cells balanced by terminal differentiation and cell death at the colon surface or small intestinal villus tips. Cyclic AMP, induced by agonists such as prostaglandin E₂ and vasoactive intestinal polypeptide, promotes proliferation and ion secretion and suppresses apoptosis in intestinal epithelial cells. Here, we show that cell differentiation in a model intestinal epithelium leads to attenuation of cAMP production in response to G protein-coupled receptor and receptor-independent agonists. Concomitantly, key components of the cAMP cascade, the α subunit of the stimulatory G protein, G_s, and adenylyl cyclase (AC) isoforms 3, 4, 6, and 7 are down-regulated. By contrast, AC1, AC2, AC8, and AC9, and the receptors for prostaglandin E₂ and vasoactive intestinal polypeptide, are not expressed or not affected by differentiation. We confirmed key findings in normal murine colon epithelium, in which the major AC isoforms and G_sα are markedly down-regulated in differentiated surface cells. Suppression of AC isoforms and G_sα is functionally important, because their constitutive expression completely reverses differentiation-induced cAMP attenuation. Thus, down-regulation of AC isoforms and G_sα is an integral part of the intestinal epithelial differentiation program, perhaps serving to release cells from cAMP-promoted anti-apoptosis as a prerequisite for cell death upon terminal differentiation.