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Parathyroid Hormone (PTH) plays a crucial role in the maintenance of calcium homeostasis directly acting on bone and kidneys and indirectly on the intestine. However, a large family of PTH-related peptides exists that exerts other physiological effects on different tissues and organs, such as the Central Nervous System (CNS). In humans, PTH-related peptides are Parathyroid Hormone (PTH), PTH-like hormones (PTHrP and PTHLH), and tuberoinfundibular peptide of 39 (TIP39 or PTH2). With different affinities, these ligands can bind parathyroid receptor type 1 (PTH1R) and type 2 (PTH2R), which are part of the type II G-protein-coupled-receptors (GPCRs) family. The PTH/PTHrP/PTH1R system has been found to be expressed in many areas of the brain (hippocampus, amygdala, hypothalamus, caudate nucleus, corpus callosum, subthalamic nucleus, thalamus, substantia nigra, cerebellum), and literature data suggest the system exercises a protective action against neuroinflammation and neurodegeneration, with positive effects on memory and hyperalgesia. TIP39 is a small peptide belonging to the PTH-related family with a high affinity for PTH2R in the CNS. The TIP39/PTH2R system has been proposed to mediate many regulatory and functional roles in the brain and to modulate auditory, nociceptive, and sexual maturation functions. This review aims to summarize the knowledge of PTH-related peptides distribution and functions in the CNS and to highlight the gaps that still need to be filled. [ABSTRACT FROM AUTHOR]

PTH revisited. Recent investigations of parathyroid hormone (PTH) have advanced our understanding of its circulating forms as well as its action. It is now clear that first-generation immunoradiometric assays of so-called intact “PTH” not only measured full-length PTH(1–84) but also recognized large PTH fragments lacking the amino-terminus. New, second generation assays detect only full-length PTH. Under diverse pathological settings, second generation assays display lower levels of PTH (1–84). By measuring full-length PTH (bioactive PTH) and the combined full-length plus amino-terminal PTH fragments, the amount of non-PTH(1–84) in circulation can be estimated. The primary amino-terminal fragment is likely to be PTH(7–84). A considerable controversy surrounds the pathological significance of PTH(7–84) and its relation to adynamic bone disease. While these findings were emerging, other work uncovered the apparent basis by which PTH receptors signal through cAMP in some instances but through Ca/inositol phosphate in others. This signaling switch is dictated by the cytoplasmic adapter protein NHERF1 (EBP50), which is expressed in a cell-selective fashion. Other provocative findings may provide a means of unifying determinations of PTH(7–84) with the effects of NHERF1 on PTH receptor signaling. These latter studies reveal that in cells expressing NHERF1, PTH(7–84) has no effect on PTH receptor signaling or internalization. However, in cells lacking or expressing low levels of NHERF1, PTH(7–84) internalizes the PTH receptor without accompanying activation. Together, these findings suggest that the accumulation of PTH(7–84) in renal failure may lead to PTH resistance by internalizing and down-regulating PTH receptors. [ABSTRACT FROM AUTHOR]