TIP39 (either human or rat) does not activate the human or rat PTH1R. This motivated investigation of the relative receptor specificity of the ligands. Therefore, not surprisingly, the three peptides do have a similar three‐dimensional structure. While the known ligands for PTH1R, parathyroid hormone (PTH) and parathyroid hormone related peptide (PTHrP) have very few amino acid residues in common with TIP39, the only known endogenous ligand for PTH2R, their receptors, the PTH1R and PTH2R have about 50% amino acid identity when their sequences are aligned. It was shown to increase cAMP as well as intracellular Ca ion levels probably via Gs and Gq proteins, respectively. Rat (and mouse as these species have the same amino acid sequence for this gene) as well as human TIP39 (different in 4 amino acids) was demonstrated to be an agonist for the rat as well as the human PTH2R. Recently developed experimental tools have stimulated further behavioural investigations, and novel results obtained are discussed in this review. In addition, TIP39 also affects the secretion of several hypothalamic hormones providing the basis for indirect behavioural actions. TIP39 probably exerts direct effect on the neuronal networks controlling these behaviours based on the localization of PTH2R and local TIP39 actions. It also influences thermoregulation and potentially auditory responses. This peptide neuromodulator system has been extensively investigated over the past 20 years including its behavioural actions, such as its role in the control of nociception, fear and fear incubation, anxiety and depression‐like behaviours, and maternal and social behaviours. The peptide is expressed in the brain by a small number of neurons with a highly restricted distribution, which in turn project to a large number of brain regions that contain PTH2R. Hence, it is also known as parathyroid hormone 2. Tuberoinfundibular peptide of 39 residues (TIP39) acts via its endogenous class B G‐protein coupled receptorthe parathyroid hormone 2 receptor (PTH2R).
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