One Single Signaling Pathway for So Many Different Biological Functions: Lessons from the Cyclic Adenosine Monophosphate/Protein Kinase A Pathway-Related Diseases

Abstract

The cAMP/protein kinase A (PKA) pathway has been the focus of intense research for 60 yr. Three Nobel prizes were directly related to this pathway, with E. W. Sutherland in 1971 for the discovery of cAMP, A. G. Gilman and M. Rodbell in 1994 for the discovery of G proteins, and R. J. Lefkowitz and B. K. Kobilka this year for their studies on G protein-coupled receptors (GPCRs) (1). The canonical pathway starts at the plasma membrane level with a receptor that belongs to the family of GPCRs, characterized by their seven-transmembrane domains (2). Upon ligand fixation, the -subunit (Gs ) of the multimeric protein Gs exchanges GDP for GTP and dissociates from the and -subunits (3). Gs further activates the adenylyl cyclase, which catalyzes the transformation of ATP into the second messenger cAMP. cAMP activates downstream the PKA by binding to its regulatory subunits. Subsequently, the PKA catalytic subunits are released and phosphorylate a broad spectrum of proteins on serine/threonine residues, among which is the transcription factor CREB (cAMP response element-binding protein) (3). Phosphodiesterases act as negative regulators of the pathway by binding cAMP (4). This pathway is present in almost all cell types and mediates a wide spectrum of biological functions. The vast variety of membrane receptors that signal directly through the cAMP/PKA pathway is also of the utmost importance in pharmacology (5, 6). In the endocrine system, the cAMP/PKA pathway is mediating signaling of many hormones, such as GnRH and gonadotropins in the gonadotroph axis, CRH and corticotropin in the corticotroph axis, TSH, GHRH, and ghrelin in the somatotroph axis; the catecholamines, PTH, and PTHrP, several neurohormones (vasopressin, serotonin, dopamine, vasoactive intestinal peptide), and incretins (glucagon, glucagon-like peptide, gastric inhibitory peptide). It is not a surprise that such an important signaling pathway for endocrine physiology can be abnormally activated or inactivated at various levels in several endocrine diseases. Roughly, the cAMP/PKA pathway inactivation is responsible for hormone resistance, whereas cAMP/PKA pathway activation is responsible for autonomous hypersecretion and tumor development. Although there are similarities between the clinical pictures of various alterations having the same global effect on the cAMP/PAKA pathway, some differences are observed. By the same token, inactivation or activation of the same gene controlling the pathway does not result in perfect mirror-image phenotypes. Inactivation of the cAMP/PKA pathway has been reported in distinct syndromes, with deficiencies of endocrine functions in the majority of cases. These alterations have been reported at different levels of the cAMP/PKA pathway. Genetic alterations at the GNAS locus—the gene coding for Gs —are responsible for a set of syndromes called type I pseudohypoparathyroidism(7).TypeIpseudohypoparathyroidism associates a dysmorphic syndrome called the Albright hereditary osteodystrophy, and hormone resistance, mainly to PTH and TSH. Albright osteodystrophy