ADCY5

{{Short description|Protein-coding gene in the species Homo sapiens}}

Adenylyl cyclase type 5 is an enzyme that in humans is encoded by the ADCY5 gene.{{cite journal | vauthors = Raimundo S, Giray J, Volff JN, Schwab M, Altenbuchner J, Ratge D, Wisser H | title = Cloning and sequence of partial cDNAs encoding the human type V and VI adenylyl cyclases and subsequent RNA-quantification in various tissues | journal = Clinica Chimica Acta; International Journal of Clinical Chemistry | volume = 285 | issue = 1–2 | pages = 155–161 | date = July 1999 | pmid = 10481931 | doi = 10.1016/S0009-8981(99)00067-4 }}{{cite web | title = Entrez Gene: ADCY5 adenylate cyclase 5| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=111}}

The human ADCY5 gene is located on the long arm of chromosome 3 and codes for the enzyme Adenylyl Cyclase 5 (AC5). This membrane protein has catalytic activity to convert adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP). In the brain, this enzyme is highly expressed in medium spiny neurons (MSNs) in the striatum. It is also found in non-neuronal cells such as cardiomyocytes and pancreatic islets. AC5 plays a role in several physiological processes including the modulation of neuronal activity particularly in the striatum, thus variants in ADCY5 gene typically lead to movement disorders.

Structure

File:AC5_structure.png

AC5 is encoded by the ADCY5 gene, located on the long arm of chromosome 3. The AC5 protein is composed of an intracytoplasmic N-terminal domain, a first membrane subdomain of 6 transmembrane segments, a first catalytic subdomain (C1a), a regulatory domain (C1b), a second membrane subdomain of 6 transmembrane segments, and a second catalytic subdomain (C2a). In contrast to other ACs, AC5 doesn't have a complete C-terminal regulatory domain (C2b). In the cytoplasm, the 2 catalytic subdomains associate to form the catalytic domain, binding ATP and converting it into cAMP. The 2 membrane subdomains are associated to form a single bundle in the plasmic membrane.{{cite journal | vauthors = Yen YC, Li Y, Chen CL, Klose T, Watts VJ, Dessauer CW, Tesmer JJ | title = Structure of adenylyl cyclase 5 in complex with Gβγ offers insights into ADCY5-related dyskinesia | journal = Nature Structural & Molecular Biology | volume = 31 | issue = 8 | pages = 1189–1197 | date = August 2024 | pmid = 38589608 | pmc = 11329361 | doi = 10.1038/s41594-024-01263-0 }} The transmembrane domain is prolonged by 2 cytoplasmic helices (H1 and H2) forming a coiled-coil domain which separates the core catalytic domain from the membrane. The conformation of the C1b regulatory and coiled-coil domains as well as their association with the various subunits of the G proteins change the dynamic conformation of the 2 catalytic subdomains and impact the catalytic activity of AC5. The N-terminal domain may participate in regulation by G proteins;{{cite journal | vauthors = Sadana R, Dascal N, Dessauer CW | title = N terminus of type 5 adenylyl cyclase scaffolds Gs heterotrimer | journal = Molecular Pharmacology | volume = 76 | issue = 6 | pages = 1256–1264 | date = December 2009 | pmid = 19783621 | pmc = 2784731 | doi = 10.1124/mol.109.058370 }}{{cite journal | vauthors = Gao X, Sadana R, Dessauer CW, Patel TB | title = Conditional stimulation of type V and VI adenylyl cyclases by G protein betagamma subunits | journal = The Journal of Biological Chemistry | volume = 282 | issue = 1 | pages = 294–302 | date = January 2007 | pmid = 17110384 | doi = 10.1074/jbc.M607522200 | doi-access = free }} however, its structural organization is only partly solved.

Function

The mammalian adenylyl cyclase family comprises nine membrane adenylyl cyclases (mACs, AC1-9), and one soluble adenylyl cyclase (sAC, AC10). As an adenylyl cyclase, AC5 catalyses the production of the second messenger cAMP from ATP, under the regulation of G proteins.{{cite journal | vauthors = Ostrom KF, LaVigne JE, Brust TF, Seifert R, Dessauer CW, Watts VJ, Ostrom RS | title = Physiological roles of mammalian transmembrane adenylyl cyclase isoforms | journal = Physiological Reviews | volume = 102 | issue = 2 | pages = 815–857 | date = April 2022 | pmid = 34698552 | pmc = 8759965 | doi = 10.1152/physrev.00013.2021 }}{{cite journal | vauthors = Dessauer CW, Watts VJ, Ostrom RS, Conti M, Dove S, Seifert R | title = International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases | journal = Pharmacological Reviews | volume = 69 | issue = 2 | pages = 93–139 | date = April 2017 | pmid = 28255005 | pmc = 5394921 | doi = 10.1124/pr.116.013078 }} The level of cellular cAMP controls the activity of protein kinase A (PKA), which phosphorylates target proteins. Upon phosphorylation, these effectors allow the cellular response to stimulation of G protein-coupled receptors (GPCR). However, AC5 differs from other mACs by its sequence and length, its expression pattern and its regulation.

AC5 has been identified as the primary AC isoform expressed in MSNs.{{cite journal | vauthors = Sanabra C, Mengod G | title = Neuroanatomical distribution and neurochemical characterization of cells expressing adenylyl cyclase isoforms in mouse and rat brain | journal = Journal of Chemical Neuroanatomy | volume = 41 | issue = 1 | pages = 43–54 | date = January 2011 | pmid = 21094251 | doi = 10.1016/j.jchemneu.2010.11.001 | hdl = 10261/73698 | hdl-access = free }} The striatum controls movement via a subtle balance between the activity of two types of MSNs: the striato-nigral MSNs of the direct pathway that facilitate movement execution and the striato-pallidal MSNs of the indirect pathway that inhibit movement execution. The synthesis of cAMP by AC5 in MSNs is finely regulated by G protein-coupled receptors. AC5 is activated by the Gαolf protein (encoded by the GNAL gene) downstream of the D1 dopamine receptor (D1R) in the direct pathway and the adenosine A_2A receptor (A_2AR) in the indirect pathway, while it is inhibited by Gαi/o downstream of the D2 dopamine receptors (D2R) in the direct pathway and the adenosine A₁ receptor (A₁R) in the indirect pathway. cAMP levels in direct/indirect MSNs are critical for the activation of their target neurons, and thus facilitation or inhibition of movement.

File:AC5_and_cAMP_signalling_pathway_in_MSNs.png

Interactions

In MSNs, AC5 associates with the heterotrimeric protein G containing Gαolf, Gβ2 and Gγ7.{{cite journal | vauthors = Hervé D | title = Identification of a specific assembly of the g protein golf as a critical and regulated module of dopamine and adenosine-activated cAMP pathways in the striatum | journal = Frontiers in Neuroanatomy | volume = 5 | pages = 48 | date = 2011 | pmid = 21886607 | pmc = 3155884 | doi = 10.3389/fnana.2011.00048 | doi-access = free }} In vitro, AC5 can also interact with Gβ1 and Gγ2 through its N-terminal domain. AC5 has been shown to interact with RGS2.{{cite journal | vauthors = Salim S, Sinnarajah S, Kehrl JH, Dessauer CW | title = Identification of RGS2 and type V adenylyl cyclase interaction sites | journal = The Journal of Biological Chemistry | volume = 278 | issue = 18 | pages = 15842–15849 | date = May 2003 | pmid = 12604604 | doi = 10.1074/jbc.M210663200 | doi-access = free }}

Clinical significance

= Mixed movement disorders =

Mixed movement disorders linked to ADCY5 (MxMD-ADCY5) is a rare childhood-onset hyperkinetic disease due to pathogenic variants in the ADCY5 gene.

== Symptoms and diagnosis ==

ADCY5-related movement disorder is named after the causative gene ADCY5, found in 2012 via whole exome sequencing.{{cite journal | vauthors = Chen YZ, Matsushita MM, Robertson P, Rieder M, Girirajan S, Antonacci F, Lipe H, Eichler EE, Nickerson DA, Bird TD, Raskind WH | title = Autosomal dominant familial dyskinesia and facial myokymia: single exome sequencing identifies a mutation in adenylyl cyclase 5 | journal = Archives of Neurology | volume = 69 | issue = 5 | pages = 630–635 | date = May 2012 | pmid = 22782511 | pmc = 3508680 | doi = 10.1001/archneurol.2012.54 }} However, the first patient's description was made in 1967 as “paroxysmal choreoathetosis”.{{cite journal | vauthors = Perez-Borja C, Tassinari AC, Swanson AG | title = Paroxysmal choreoathetosis and seizures induced by movement (reflex epilepsy) | journal = Epilepsia | volume = 8 | issue = 4 | pages = 260–270 | date = December 1967 | pmid = 5238718 | doi = 10.1111/j.1528-1157.1967.tb04442.x }} This case and her family history were reappraised when her daughter started to have similar manifestations, then described as “familial dyskinesia with facial myokymia”.{{cite journal | vauthors = Fernandez M, Raskind W, Wolff J, Matsushita M, Yuen E, Graf W, Lipe H, Bird T | title = Familial dyskinesia and facial myokymia (FDFM): a novel movement disorder | journal = Annals of Neurology | volume = 49 | issue = 4 | pages = 486–492 | date = April 2001 | doi = 10.1002/ana.98 | pmid = 11310626 | url = https://pubmed.ncbi.nlm.nih.gov/11310626 }} This disease is presently referred to as MxMD-ADCY5 since the phenotypic spectrum has been more extensively studied.{{cite journal | vauthors = Chen DH, Méneret A, Friedman JR, Korvatska O, Gad A, Bonkowski ES, Stessman HA, Doummar D, Mignot C, Anheim M, Bernes S, Davis MY, Damon-Perrière N, Degos B, Grabli D, Gras D, Hisama FM, Mackenzie KM, Swanson PD, Tranchant C, Vidailhet M, Winesett S, Trouillard O, Amendola LM, Dorschner MO, Weiss M, Eichler EE, Torkamani A, Roze E, Bird TD, Raskind WH | title = ADCY5-related dyskinesia: Broader spectrum and genotype-phenotype correlations | journal = Neurology | volume = 85 | issue = 23 | pages = 2026–2035 | date = December 2015 | pmid = 26537056 | pmc = 4676753 | doi = 10.1212/WNL.0000000000002058 }} Indeed, the clinical spectrum is very broad and is typically characterized by a variable combination of permanent and paroxysmal hyperkinetic movements such as myoclonus, chorea, tremor and/or dystonia.{{cite journal | vauthors = Menon PJ, Nilles C, Silveira-Moriyama L, Yuan R, de Gusmao CM, Münchau A, Carecchio M, Grossman S, Grossman G, Méneret A, Roze E, Pringsheim T | title = Scoping Review on ADCY5-Related Movement Disorders | journal = Movement Disorders Clinical Practice | volume = 10 | issue = 7 | pages = 1048–1059 | date = July 2023 | pmid = 37476318 | pmc = 10354615 | doi = 10.1002/mdc3.13796 }} These symptoms can be more or less severe but, in most cases, hamper the quality of life of patients. The occurrence of paroxysmal nocturnal dyskinesias and the presence of perioral twitches are particularly suggestive of the diagnosis. These dyskinesias are sometimes associated with other symptoms such as axial hypotonia, speech disturbance, oculomotor signs, pyramidal syndrome, developmental delay, psychiatric disorders or intellectual disability.{{cite journal | vauthors = Chang FC, Westenberger A, Dale RC, Smith M, Pall HS, Perez-Dueñas B, Grattan-Smith P, Ouvrier RA, Mahant N, Hanna BC, Hunter M, Lawson JA, Max C, Sachdev R, Meyer E, Crimmins D, Pryor D, Morris JG, Münchau A, Grozeva D, Carss KJ, Raymond L, Kurian MA, Klein C, Fung VS | title = Phenotypic insights into ADCY5-associated disease | journal = Movement Disorders | volume = 31 | issue = 7 | pages = 1033–1040 | date = July 2016 | pmid = 27061943 | pmc = 4950003 | doi = 10.1002/mds.26598 }} Likewise, a few patients have been reported with heart failure, raising the possibility of cardiac involvement.{{cite journal | vauthors = Vijiaratnam N, Bhatia KP, Lang AE, Raskind WH, Espay AJ | title = ADCY5-Related Dyskinesia: Improving Clinical Detection of an Evolving Disorder | journal = Movement Disorders Clinical Practice | volume = 6 | issue = 7 | pages = 512–520 | date = September 2019 | pmid = 31538084 | pmc = 6749814 | doi = 10.1002/mdc3.12816 }}File:MxMD-ADCY5_variants.png

== Genetics ==

MxMD-ADCY5 is most often transmitted in an autosomal dominant manner and more rarely autosomal recessive.{{cite journal | vauthors = Bohlega SA, Abou-Al-Shaar H, AlDakheel A, Alajlan H, Bohlega BS, Meyer BF, Monies D, Cupler EJ, Al-Saif AM | title = Autosomal recessive ADCY5-Related dystonia and myoclonus: Expanding the genetic spectrum of ADCY5-Related movement disorders | journal = Parkinsonism & Related Disorders | volume = 64 | pages = 145–149 | date = July 2019 | pmid = 30975617 | doi = 10.1016/j.parkreldis.2019.02.039 }} The occurrence of somatic mosaicism is unexpectedly frequent in MxMD-ADCY5, with a less severe phenotype. The most described causal variant is the dominant mutation R418W situated in the coiled-coil domain of AC5. Most of the known variants are concentrated in the coiled-coil, catalytic (C1a and C2a) and regulatory (C1b) domains of AC5 suggesting a dysregulation of its enzymatic activity in patients.

== Pathophysiology ==

The pathophysiology of this disease is based on a deregulation of the cAMP pathway in the striatum linked to ADCY5 mutations, disrupting the balance between the direct and indirect pathways of movement control. In vitro functional studies have shown a gain of function for several dominant non-truncating mutations altering cAMP production after G protein-coupled receptors stimulation compared to wildtype AC5.{{cite journal | vauthors = Chen YZ, Friedman JR, Chen DH, Chan GC, Bloss CS, Hisama FM, Topol SE, Carson AR, Pham PH, Bonkowski ES, Scott ER, Lee JK, Zhang G, Oliveira G, Xu J, Scott-Van Zeeland AA, Chen Q, Levy S, Topol EJ, Storm D, Swanson PD, Bird TD, Schork NJ, Raskind WH, Torkamani A | title = Gain-of-function ADCY5 mutations in familial dyskinesia with facial myokymia | journal = Annals of Neurology | volume = 75 | issue = 4 | pages = 542–549 | date = April 2014 | pmid = 24700542 | pmc = 4457323 | doi = 10.1002/ana.24119 }}{{cite journal | vauthors = Doyle TB, Hayes MP, Chen DH, Raskind WH, Watts VJ | title = Functional characterization of AC5 gain-of-function variants: Impact on the molecular basis of ADCY5-related dyskinesia | journal = Biochemical Pharmacology | volume = 163 | pages = 169–177 | date = May 2019 | pmid = 30772269 | pmc = 6470011 | doi = 10.1016/j.bcp.2019.02.005 }} The pathophysiology of truncating and/or recessive variants is poorly known.

== Treatment ==

The pathophysiological mechanisms and preliminary evidence designate adenosine A_2A receptors’ antagonists, namely caffeine,{{cite journal | vauthors = Méneret A, Mohammad SS, Cif L, Doummar D, DeGusmao C, Anheim M, Barth M, Damier P, Demonceau N, Friedman J, Gallea C, Gras D, Gurgel-Giannetti J, Innes EA, Necpál J, Riant F, Sagnes S, Sarret C, Seliverstov Y, Paramanandam V, Shetty K, Tranchant C, Doulazmi M, Vidailhet M, Pringsheim T, Roze E | title = Efficacy of Caffeine in ADCY5-Related Dyskinesia: A Retrospective Study | journal = Movement Disorders | volume = 37 | issue = 6 | pages = 1294–1298 | date = June 2022 | pmid = 35384065 | doi = 10.1002/mds.29006 }} istradefylline and theophylline, as potential first line treatments. Symptomatic treatment with benzodiazepine might also be useful to some patients, especially to treat nighttime dyskinesia. In severe forms, bilateral deep brain stimulation of the globus pallidus internus (GPi-DBS) could be considered, with variable outcomes.{{cite journal | vauthors = de Almeida Marcelino AL, Mainka T, Krause P, Poewe W, Ganos C, Kühn AA | title = Deep brain stimulation reduces (nocturnal) dyskinetic exacerbations in patients with ADCY5 mutation: a case series | journal = Journal of Neurology | volume = 267 | issue = 12 | pages = 3624–3631 | date = December 2020 | pmid = 32647899 | pmc = 7674568 | doi = 10.1007/s00415-020-09871-8 }}{{cite journal | vauthors = Cif L, Demailly D, Gehin C, Chan Seng E, Dornadic M, Huby S, Poulen G, Roubertie A, Villessot M, Roujeau T, Coubes P | title = Deep brain stimulation effect in genetic dyskinetic cerebral palsy: The case of ADCY5- related disease | journal = Molecular Genetics and Metabolism | volume = 138 | issue = 1 | pages = 106970 | date = January 2023 | pmid = 36610259 | doi = 10.1016/j.ymgme.2022.106970 }}

= Other clinical implications =

ADCY5 polymorphisms are also associated with neuropsychiatric and central nervous system disorders, notably alcoholism,{{cite journal | vauthors = Kim KS, Kim H, Baek IS, Lee KW, Han PL | title = Mice lacking adenylyl cyclase type 5 (AC5) show increased ethanol consumption and reduced ethanol sensitivity | journal = Psychopharmacology | volume = 215 | issue = 2 | pages = 391–398 | date = May 2011 | pmid = 21193983 | doi = 10.1007/s00213-010-2143-x }} depression{{cite journal | vauthors = Procopio DO, Saba LM, Walter H, Lesch O, Skala K, Schlaff G, Vanderlinden L, Clapp P, Hoffman PL, Tabakoff B | title = Genetic markers of comorbid depression and alcoholism in women | journal = Alcoholism: Clinical and Experimental Research | volume = 37 | issue = 6 | pages = 896–904 | date = June 2013 | pmid = 23278386 | pmc = 3620932 | doi = 10.1111/acer.12060 }} or autism.{{cite journal | vauthors = Kim H, Lee Y, Park JY, Kim JE, Kim TK, Choi J, Lee JE, Lee EH, Kim D, Kim KS, Han PL | title = Loss of Adenylyl Cyclase Type-5 in the Dorsal Striatum Produces Autistic-Like Behaviors | journal = Molecular Neurobiology | volume = 54 | issue = 10 | pages = 7994–8008 | date = December 2017 | pmid = 27878759 | doi = 10.1007/s12035-016-0256-x }}

ADCY5 seems to play a role in cardiac function and may be involved in both longevity and stress resistance. Indeed, mice with a complete depletion of ADCY5 live significantly longer than control littermates and are resistant to cardiac stress.{{cite journal | vauthors = Yan L, Vatner DE, O'Connor JP, Ivessa A, Ge H, Chen W, Hirotani S, Ishikawa Y, Sadoshima J, Vatner SF | title = Type 5 adenylyl cyclase disruption increases longevity and protects against stress | journal = Cell | volume = 130 | issue = 2 | pages = 247–258 | date = July 2007 | pmid = 17662940 | doi = 10.1016/j.cell.2007.05.038 }}{{cite journal | vauthors = Vatner SF, Park M, Yan L, Lee GJ, Lai L, Iwatsubo K, Ishikawa Y, Pessin J, Vatner DE | title = Adenylyl cyclase type 5 in cardiac disease, metabolism, and aging | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 305 | issue = 1 | pages = H1–H8 | date = July 2013 | pmid = 23624627 | pmc = 3727099 | doi = 10.1152/ajpheart.00080.2013 }}{{cite journal | vauthors = Vatner DE, Yan L, Lai L, Yuan C, Mouchiroud L, Pachon RE, Zhang J, Dillinger JG, Houtkooper RH, Auwerx J, Vatner SF | title = Type 5 adenylyl cyclase disruption leads to enhanced exercise performance | journal = Aging Cell | volume = 14 | issue = 6 | pages = 1075–1084 | date = December 2015 | pmid = 26424149 | pmc = 4693460 | doi = 10.1111/acel.12401 }}

References

External links

{{UCSC gene info|ADCY5}}
[https://www.adcy5.org/ ADCY5.org]
Paris Brain Institute : [https://parisbraininstitute.org/news/coffee-treat-form-dyskinesia research on MxMD-ADCY5]