{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Adenylyl cyclase 4 (ADCY4) is emerging as an important regulator of cyclic AMP (cAMP) signaling in a variety of cell types and organs. In the olfactory epilia, ADCY4 is one of several cyclase isoforms present in sensory cilia, although odor‐evoked responses depend predominantly on AC3 rather than ADCY4."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In human bronchial smooth muscle cells, ADCY4 is expressed in non–lipid raft membrane domains and contributes to receptor‐mediated cAMP production that is differentially modulated by Ca²⁺ and G protein βγ subunits."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In adrenocortical Y1 cells, ADCY4 expression is controlled by a conserved promoter region that integrates signals from transcription factors such as specificity proteins and steroidogenic factor 1 (SF1). In several forskolin‐resistant Y1 cell mutants, loss of ADCY4 was identified as the culprit for impaired cAMP production and altered cellular morphology; reintroduction of ADCY4 restored both cAMP signaling and normal phenotype."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Moreover, ADCY4 protein levels are additionally regulated through ubiquitination by an XIAP/TRIP-Br1 complex that targets a conserved lysine residue, thereby providing a negative feedback loop to maintain cAMP homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n ADCY4 is also expressed in immune and stromal cells. For instance, although its rapid downregulation is observed in monocytes from young males, its specific role there contrasts with related isoforms, while in senescent fibroblasts, ADCY4 associates with calcium-dependent protein kinase C isoforms via AKAP scaffolds to modulate basal and stimulated cAMP levels."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the cardiovascular system, reduced ADCY4 expression in cardiomyocytes has been linked to Klotho deficiency–induced heart failure; conversely, cardiac-specific restoration of ADCY4 improves myocardial performance by enhancing cAMP/PKA signaling that regulates calcium handling and mitochondrial function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Similarly, in vascular arterioles, elevated ADCY4 expression in response to increased shear stress during exercise suggests a role in mechanoresponsive vascular remodeling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the central nervous system, ADCY4 is prominently expressed in the medial prefrontal cortex, where it colocalizes with dopamine D1-like receptors. Here, ADCY4 plays a critical role in facilitating cAMP production and potentiating cAMP-responsive element binding protein phosphorylation following coactivation of dopaminergic and muscarinic receptors, thereby influencing cognitive signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, genetic studies in the parasitic nematode Haemonchus contortus demonstrate polymorphic variation in the AC-4 gene, suggesting that evolutionary changes in ADCY4 may also influence parasite biology."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these studies highlight the multifaceted functions of ADCY4 in regulating cAMP-mediated signal transduction across diverse tissues and underscore its potential as a therapeutic target in disorders ranging from heart failure and immune dysregulation to cognitive impairment.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "S T Wong, K Trinh, B Hacker, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Disruption of the type III adenylyl cyclase gene leads to peripheral and behavioral anosmia in transgenic mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neuron (2000)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0896-6273(00)00060-x"}], "href": "https://doi.org/10.1016/s0896-6273(00"}, {"type": "t", "text": "00060-x) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11055432"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11055432"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Amy S Bogard, Congfeng Xu, Rennolds S Ostrom "}, {"type": "b", "children": [{"type": "t", "text": "Human bronchial smooth muscle cells express adenylyl cyclase isoforms 2, 4, and 6 in distinct membrane microdomains."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Pharmacol Exp Ther (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1124/jpet.110.177923"}], "href": "https://doi.org/10.1124/jpet.110.177923"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21228062"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21228062"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Bernard P Schimmer, Jennivine Tsao, Martha Cordova, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Contributions of steroidogenic factor 1 to the transcription landscape of Y1 mouse adrenocortical tumor cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Endocrinol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.mce.2010.11.024"}], "href": "https://doi.org/10.1016/j.mce.2010.11.024"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21111771"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21111771"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Abdallah Al-Hakim, Xianliang Rui, Jennivine Tsao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Forskolin-resistant Y1 adrenal cell mutants are deficient in adenylyl cyclase type 4."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Endocrinol (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.mce.2003.10.066"}], "href": "https://doi.org/10.1016/j.mce.2003.10.066"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15062554"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15062554"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Wenbao Hu, Xiaojie Yu, Zhengzhao Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The complex of TRIP-Br1 and XIAP ubiquitinates and degrades multiple adenylyl cyclase isoforms."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Elife (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7554/eLife.28021"}], "href": "https://doi.org/10.7554/eLife.28021"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28656888"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28656888"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Petter K Risøe, Arkady Rutkovskiy, Joanna Ågren, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Higher TNFα responses in young males compared to females are associated with attenuation of monocyte adenylyl cyclase expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Immunol (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.humimm.2015.03.018"}], "href": "https://doi.org/10.1016/j.humimm.2015.03.018"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25959651"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25959651"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Ji-Heon Rhim, Ik-Soon Jang, Eui-Ju Yeo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Role of protein kinase C-dependent A-kinase anchoring proteins in lysophosphatidic acid-induced cAMP signaling in human diploid fibroblasts."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Aging Cell (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1474-9726.2006.00239.x"}], "href": "https://doi.org/10.1111/j.1474-9726.2006.00239.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17081159"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17081159"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Kai Chen, Shirley Wang, Zhongjie Sun "}, {"type": "b", "children": [{"type": "t", "text": "In Vivo Cardiac-specific Expression of Adenylyl Cyclase 4 Gene Protects against Klotho Deficiency-induced Heart Failure."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Transl Res (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.trsl.2022.01.006"}], "href": "https://doi.org/10.1016/j.trsl.2022.01.006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35114419"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35114419"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "M Harold Laughlin, Hsiao T Yang, Darla L Tharp, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Vascular cell transcriptomic changes to exercise training differ directionally along and between skeletal muscle arteriolar trees."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Microcirculation (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/micc.12336"}], "href": "https://doi.org/10.1111/micc.12336"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27889934"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27889934"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Maria C Olianas, Simona Dedoni, Pierluigi Onali "}, {"type": "b", "children": [{"type": "t", "text": "Coincidence signaling of dopamine D1-like and M1 muscarinic receptors in the regulation of cyclic AMP formation and CREB phosphorylation in mouse prefrontal cortex."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurosignals (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1159/000335208"}], "href": "https://doi.org/10.1159/000335208"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22456324"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22456324"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Youchang Liu, Tadashi Iwasaki, Shinobu Watarai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Effect of turpentine oil on C-reactive protein (CRP) production in rainbow trout (Oncorhynchus mykiss)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Fish Shellfish Immunol (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.fsi.2004.03.003"}], "href": "https://doi.org/10.1016/j.fsi.2004.03.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15276600"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15276600"}]}]}]}