{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n The growth hormone‐releasing hormone receptor (GHRHR) is a class B G‐protein–coupled receptor that mediates the actions of its ligand, growth hormone–releasing hormone (GHRH), to regulate growth hormone (GH) synthesis and secretion from pituitary somatotropes. Mutations in the GHRHR gene cause isolated GH deficiency (IGHD) in humans, resulting in proportionate short stature and metabolic alterations, as documented in familial as well as sporadic cases (e.g."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " High‐resolution cryo–electron microscopy studies of the human receptor have now elucidated the molecular basis of peptide recognition and receptor activation; these findings further explain how IGHD‐causing mutations impair receptor function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n GHRHR expression in somatotropes is not only critical for proper endocrine control of growth but is also subject to modulation by hormonal factors; for example, estradiol replacement has been shown to upregulate GHRHR expression and improve GH synthesis in estrogen‐deficient models."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " In addition to its classical endocrine role, alternative splice variants of GHRHR, such as SV1, have been identified in various cancers. These variants display ligand–dependent as well as intrinsic activity that promotes cell proliferation through the activation of signaling cascades including mitogen–activated protein kinase (MAPK) and downstream effectors."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its role in the pituitary, GHRHR signaling has been implicated in extra–pituitary responses. For instance, GHRHR is expressed in cardiac stem cells where stimulation by its agonists promotes proliferation and survival via ERK and AKT pathways."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Moreover, the splice variant SV1 has been shown to contribute to oncogenic processes in several cancers by activating MAPK cascades"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "and by engaging the JAK2/STAT3 pathway to modulate proliferation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Clinical and genetic studies in IGHD patients and in idiopathic short stature cohorts further underscore the pivotal role of GHRHR in growth regulation; such investigations also reveal that naturally occurring genetic variants in GHRHR may influence systemic GH levels and even mammographic density, thereby affecting breast tissue characteristics."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "14"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, GHRHR functions as a central mediator of GH release, with its precise ligand–receptor interactions critical for normal growth and metabolism. Alterations in its expression or structure not only disrupt endocrine homeostasis leading to growth deficiencies, but also contribute to oncogenic signaling and tissue repair processes. This multifunctional receptor thus represents a key target for therapeutic intervention in growth disorders, certain cancers, and regenerative medicine.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Kyriaki S Alatzoglou, James P Turton, Daniel Kelberman, et al. 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