Biology:ADCY5

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Short description: Protein-coding gene in the species Homo sapiens

A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Adenylyl cyclase type 5 is an enzyme that in humans is encoded by the ADCY5 gene.[1][2]

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

AC5 is a transmembrane protein with a cytoplasmic catalytic domain separated from the membrane by a coiled-coil stem which is part of its regulatory domain

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.[3] 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;[4][5] 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.[6][7] 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.[8] 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 A2A receptor (A2AR) in the indirect pathway, while it is inhibited by Gαi/o downstream of the D2 dopamine receptors (D2R) in the indirect pathway and the adenosine A1 receptor (A1R) in the direct pathway. cAMP levels in direct/indirect MSNs are critical for the activation of their target neurons, and thus facilitation or inhibition of movement.

AC5 is the key enzyme in the cAMP signalling pathway responding to dopamine and adenosine in MSNs

Interactions

In MSNs, AC5 associates with the heterotrimeric protein G containing Gαolf, Gβ2 and Gγ7.[9] In vitro, AC5 can also interact with Gβ1 and Gγ2 through its N-terminal domain. AC5 has been shown to interact with RGS2.[10]

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.[11] However, the first patient's description was made in 1967 as “paroxysmal choreoathetosis”.[12] This case and her family history were reappraised when her daughter started to have similar manifestations, then described as “familial dyskinesia with facial myokymia”.[13] This disease is presently referred to as MxMD-ADCY5 since the phenotypic spectrum has been more extensively studied.[14] 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.[15] 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.[16] Likewise, a few patients have been reported with heart failure, raising the possibility of cardiac involvement.[17]

Missense and small indels variants associated with MxMD-ADCY5 Dominant variant / Recessive variant

Genetics

MxMD-ADCY5 is most often transmitted in an autosomal dominant manner and more rarely autosomal recessive.[18] The occurrence of somatic mosaicism[14] is unexpectedly frequent in MxMD-ADCY5, with a less severe phenotype.[15] 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.[19][20] The pathophysiology of truncating and/or recessive variants is poorly known.

Treatment

The pathophysiological mechanisms and preliminary evidence designate adenosine A2A receptors’ antagonists, namely caffeine,[21] istradefylline and theophylline, as potential first line treatments. Symptomatic treatment with benzodiazepine might also be useful to some patients, especially to treat nighttime dyskinesia.[15] In severe forms, bilateral deep brain stimulation of the globus pallidus internus (GPi-DBS) could be considered, with variable outcomes.[22][23]

Other clinical implications

ADCY5 polymorphisms are also associated with neuropsychiatric and central nervous system disorders, notably alcoholism,[24] depression[25] or autism.[26]

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.[27][28][29]

References

  1. ↑ "Cloning and sequence of partial cDNAs encoding the human type V and VI adenylyl cyclases and subsequent RNA-quantification in various tissues". Clinica Chimica Acta; International Journal of Clinical Chemistry 285 (1–2): 155–161. July 1999. doi:10.1016/S0009-8981(99)00067-4. PMID 10481931. 
  2. ↑ "Entrez Gene: ADCY5 adenylate cyclase 5". https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=111. 
  3. ↑ "Structure of adenylyl cyclase 5 in complex with Gβγ offers insights into ADCY5-related dyskinesia". Nature Structural & Molecular Biology 31 (8): 1189–1197. August 2024. doi:10.1038/s41594-024-01263-0. PMID 38589608. 
  4. ↑ "N terminus of type 5 adenylyl cyclase scaffolds Gs heterotrimer". Molecular Pharmacology 76 (6): 1256–1264. December 2009. doi:10.1124/mol.109.058370. PMID 19783621. 
  5. ↑ "Conditional stimulation of type V and VI adenylyl cyclases by G protein betagamma subunits". The Journal of Biological Chemistry 282 (1): 294–302. January 2007. doi:10.1074/jbc.M607522200. PMID 17110384. 
  6. ↑ "Physiological roles of mammalian transmembrane adenylyl cyclase isoforms". Physiological Reviews 102 (2): 815–857. April 2022. doi:10.1152/physrev.00013.2021. PMID 34698552. 
  7. ↑ "International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases". Pharmacological Reviews 69 (2): 93–139. April 2017. doi:10.1124/pr.116.013078. PMID 28255005. 
  8. ↑ "Neuroanatomical distribution and neurochemical characterization of cells expressing adenylyl cyclase isoforms in mouse and rat brain". Journal of Chemical Neuroanatomy 41 (1): 43–54. January 2011. doi:10.1016/j.jchemneu.2010.11.001. PMID 21094251. 
  9. ↑ "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". Frontiers in Neuroanatomy 5: 48. 2011. doi:10.3389/fnana.2011.00048. PMID 21886607. 
  10. ↑ "Identification of RGS2 and type V adenylyl cyclase interaction sites". The Journal of Biological Chemistry 278 (18): 15842–15849. May 2003. doi:10.1074/jbc.M210663200. PMID 12604604. 
  11. ↑ "Autosomal dominant familial dyskinesia and facial myokymia: single exome sequencing identifies a mutation in adenylyl cyclase 5". Archives of Neurology 69 (5): 630–635. May 2012. doi:10.1001/archneurol.2012.54. PMID 22782511. 
  12. ↑ "Paroxysmal choreoathetosis and seizures induced by movement (reflex epilepsy)". Epilepsia 8 (4): 260–270. December 1967. doi:10.1111/j.1528-1157.1967.tb04442.x. PMID 5238718. 
  13. ↑ "Familial dyskinesia and facial myokymia (FDFM): a novel movement disorder". Annals of Neurology 49 (4): 486–492. April 2001. doi:10.1002/ana.98. PMID 11310626. 
  14. ↑ 14.0 14.1 "ADCY5-related dyskinesia: Broader spectrum and genotype-phenotype correlations". Neurology 85 (23): 2026–2035. December 2015. doi:10.1212/WNL.0000000000002058. PMID 26537056. 
  15. ↑ 15.0 15.1 15.2 "Scoping Review on ADCY5-Related Movement Disorders". Movement Disorders Clinical Practice 10 (7): 1048–1059. July 2023. doi:10.1002/mdc3.13796. PMID 37476318. 
  16. ↑ "Phenotypic insights into ADCY5-associated disease". Movement Disorders 31 (7): 1033–1040. July 2016. doi:10.1002/mds.26598. PMID 27061943. 
  17. ↑ "ADCY5-Related Dyskinesia: Improving Clinical Detection of an Evolving Disorder". Movement Disorders Clinical Practice 6 (7): 512–520. September 2019. doi:10.1002/mdc3.12816. PMID 31538084. 
  18. ↑ "Autosomal recessive ADCY5-Related dystonia and myoclonus: Expanding the genetic spectrum of ADCY5-Related movement disorders". Parkinsonism & Related Disorders 64: 145–149. July 2019. doi:10.1016/j.parkreldis.2019.02.039. PMID 30975617. 
  19. ↑ "Gain-of-function ADCY5 mutations in familial dyskinesia with facial myokymia". Annals of Neurology 75 (4): 542–549. April 2014. doi:10.1002/ana.24119. PMID 24700542. 
  20. ↑ "Functional characterization of AC5 gain-of-function variants: Impact on the molecular basis of ADCY5-related dyskinesia". Biochemical Pharmacology 163: 169–177. May 2019. doi:10.1016/j.bcp.2019.02.005. PMID 30772269. 
  21. ↑ "Efficacy of Caffeine in ADCY5-Related Dyskinesia: A Retrospective Study". Movement Disorders 37 (6): 1294–1298. June 2022. doi:10.1002/mds.29006. PMID 35384065. 
  22. ↑ "Deep brain stimulation reduces (nocturnal) dyskinetic exacerbations in patients with ADCY5 mutation: a case series". Journal of Neurology 267 (12): 3624–3631. December 2020. doi:10.1007/s00415-020-09871-8. PMID 32647899. 
  23. ↑ "Deep brain stimulation effect in genetic dyskinetic cerebral palsy: The case of ADCY5- related disease". Molecular Genetics and Metabolism 138 (1). January 2023. doi:10.1016/j.ymgme.2022.106970. PMID 36610259. 
  24. ↑ "Mice lacking adenylyl cyclase type 5 (AC5) show increased ethanol consumption and reduced ethanol sensitivity". Psychopharmacology 215 (2): 391–398. May 2011. doi:10.1007/s00213-010-2143-x. PMID 21193983. 
  25. ↑ "Genetic markers of comorbid depression and alcoholism in women". Alcoholism: Clinical and Experimental Research 37 (6): 896–904. June 2013. doi:10.1111/acer.12060. PMID 23278386. 
  26. ↑ "Loss of Adenylyl Cyclase Type-5 in the Dorsal Striatum Produces Autistic-Like Behaviors". Molecular Neurobiology 54 (10): 7994–8008. December 2017. doi:10.1007/s12035-016-0256-x. PMID 27878759. 
  27. ↑ "Type 5 adenylyl cyclase disruption increases longevity and protects against stress". Cell 130 (2): 247–258. July 2007. doi:10.1016/j.cell.2007.05.038. PMID 17662940. 
  28. ↑ "Adenylyl cyclase type 5 in cardiac disease, metabolism, and aging". American Journal of Physiology. Heart and Circulatory Physiology 305 (1): H1–H8. July 2013. doi:10.1152/ajpheart.00080.2013. PMID 23624627. 
  29. ↑ "Type 5 adenylyl cyclase disruption leads to enhanced exercise performance". Aging Cell 14 (6): 1075–1084. December 2015. doi:10.1111/acel.12401. PMID 26424149. 

Further reading



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