Pseudohypoparathyroidism: From Bedside to Bench and Back

ONE APPROACH TO the investigation of metabolic disorders relies upon transfer of the clinical problem to the laboratory, where both insight and technology can be rigorously applied in a controlled environment. For the medical scientist, ultimate resolution of the metabolic disorder will of course require the successful translation of the laboratory discovery to clinical usefulness, a process often described as “bench to bedside. ” This approach has been applied to the study of many endocrine disorders, including pseudohypoparathyroidism (PHP), an unusual condition in which biochemical hypoparathyroidism (i.e., hypocalcemia and hyperphosphatemia) arises from the failure of target tissues to respond appropriately to the biological actions of parathyroid hormone (PTH). Thus the pathophysiology of PHP differs fundamentally from true hypoparathyroidism, in which PTH secretion rather than PTH responsiveness is defective. More than 50 years have passed since Fuller Albright and his associates first described the failure of patients with PHP to show either a calcemic or a phosphaturic response to administered parathyroid extract. These early clinical studies led to the hypothesis that PHP is due to a defect in PTH signaling but could not even begin to anticipate the complexity of that signaling process! The PTH signal transduction cascade consists of at least three membrane-bound components: receptors that detect ligand in extracellular milieu, signal generating enzymes such as adenylyl cyclase, and the heterotrimeric (a, b, g) G proteins (reviewed elsewhere). The classical PTH receptor that is expressed in bone and kidney is a ∼75 kDa glycoprotein that is often referred to as the PTH/parathyroid hormone receptor protein (PTHrP) or type 1 PTH receptor (PTHr). The type 1 PTHr binds both PTH and PTHrP, a factor made by diverse tumors that cause humorally mediated hypercalcemia, with equivalent affinity, which accounts for the similar activities of both hormones. By contrast, a second PTH receptor, termed the type 2 receptor protein, is not expressed in conventional PTH target tissues (i.e., bone and kidney) and interacts with PTH but not PTHrP. Both PTHrs are members of a large family of receptors that can bind hormones, neurotransmitters, cytokines, light photons, taste and odor molecules. These receptors consist of a single polypeptide chain that is predicted by hydrophobicity plots to span the plasma membrane seven times (i.e., heptahelical), forming three extracellular and three or four intracellular loops and a cytoplasmic carboxy-terminal tail. The heptahelical receptors are coupled by G proteins to signal effector molecules localized to the inner surface of the plasma membrane. Highly specific associations among at least 20 a, 6 b, and 12 g chains generate a diversity of heterotrimeric G proteins that have the ability to discriminate among a multitude of receptor and effector molecules. Hormone binding to a receptor facilitates activation of the G protein, a process in which the a chain exchanges bound GDP for GTP and dissociates from the bg dimer and the receptor. The free, GTP-bound form of the a chain is the primary modulator of relevant effector molecules, although bg dimers can also influence activity of many effectors (e.g., some forms of adenylyl cyclase and phospholipase C). An intrinsic GTPase associated with the a chain acts as a molecular timing mechanism, and after a predetermined interval, GTP is hydrolyzed to GDP. The inactive GDP-bound a chain reassociates with a bg dimer, and the heterotrimeric G protein is ready for another cycle of hormone activation. Interaction of PTH with its receptor activates intracellular signal effector systems that generate the second messengers cAMP, inositol 1,4,5-trisphosphate and diacylglycerol, and cytosolic calcium. The best characterized mediator of PTH action is cAMP, which rapidly activates protein kinase A. The relevant target proteins that are phosphorylated by protein kinase A and the precise mode(s) of action of these proteins remain uncharacterized, though proteins that activate genes responsive to cAMP and ion channel proteins are strong candidates. In contrast