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Calcium signaling in neurodevelopment and pathophysiology of autism spectrum disorders

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Abstract

Background

Autism spectrum disorder (ASD) covers a group of neurodevelopmental disorders with complex genetic background. Several genetic mutations, epigenetic alterations, copy number variations and single nucleotide polymorphisms have been reported that cause ASD or modify its phenotype. Among signaling pathways that influence pathogenesis of ASD, calcium signaling has a prominent effect.

Methods

We searched PubMed and Google Scholar databases with key words “Calcium signaling” and “Autism spectrum disorder”.

Conclusion

This type of signaling has essential roles in the cell physiology. Endoplasmic reticulum and mitochondria are the key organelles involved in this signaling. It is vastly accepted that organellar disorders intensely influence the central nervous system (CNS). Several lines of evidence indicate alterations in the function of calcium channels in polygenic disorders affecting CNS. In the current review, we describe the role of calcium signaling in normal function of CNS and pathophysiology of ASD.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. American Psychiatric Association D, Association AP (2013) Diagnostic and statistical manual of mental disorders: DSM-5. American Psychiatric Association, Washington

    Book  Google Scholar 

  2. Maenner MJ, Shaw KA, Baio J (2020) Prevalence of autism spectrum disorder among children aged 8 years—autism and developmental disabilities monitoring network, 11 sites, United States, 2016. MMWR Surveill Summ 69(4):1

    Article  PubMed  PubMed Central  Google Scholar 

  3. Baio J, Wiggins L, Christensen DL, Maenner MJ, Daniels J, Warren Z et al (2018) Prevalence of autism spectrum disorder among children aged 8 years—autism and developmental disabilities monitoring network, 11 sites, United States, 2014. MMWR Surveill Summ 67(6):1

    Article  PubMed  PubMed Central  Google Scholar 

  4. Rylaarsdam L, Guemez-Gamboa A (2019) Genetic causes and modifiers of autism spectrum disorder. Front Cell Neurosci. https://doi.org/10.3389/fncel.2019.00385

    Article  PubMed  PubMed Central  Google Scholar 

  5. Gillberg C, Wahlström J (1985) Chromosome abnormalities in infantile autism and other childhood psychoses: a population study of 66 cases. Dev Med Child Neurol 27(3):293–304

    Article  CAS  PubMed  Google Scholar 

  6. Persico A, D’agruma L, Maiorano N, Totaro A, Militerni R, Bravaccio C et al (2001) Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder. Mol Psychiatry 6(2):150–159

    Article  CAS  PubMed  Google Scholar 

  7. Strømme P, Mangelsdorf ME, Scheffer IE, Gécz J (2002) Infantile spasms, dystonia, and other X-linked phenotypes caused by mutations in Aristaless related homeobox gene. ARX Brain Dev 24(5):266–268

    Article  PubMed  Google Scholar 

  8. Carney RM, Wolpert CM, Ravan SA, Shahbazian M, Ashley-Koch A, Cuccaro ML et al (2003) Identification of MeCP2 mutations in a series of females with autistic disorder. Pediatr Neurol 28(3):205–211

    Article  PubMed  Google Scholar 

  9. Jamain S, Quach H, Betancur C, Råstam M, Colineaux C, Gillberg IC et al (2003) Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat Genet 34(1):27–29

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Serajee F, Nabi R, Zhong H, Huq AM (2003) Association of INPP1, PIK3CG, and TSC2 gene variants with autistic disorder: implications for phosphatidylinositol signalling in autism. J Med Genet 40(11):e119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Jiang Yh, Sahoo T, Michaelis RC, Bercovich D, Bressler J, Kashork CD et al (2004) A mixed epigenetic/genetic model for oligogenic inheritance of autism with a limited role for UBE3A. Am J Med Genet A 131(1):1–10

    Article  PubMed  Google Scholar 

  12. Giovedí S, Corradi A, Fassio A, Benfenati F (2014) Involvement of synaptic genes in the pathogenesis of autism spectrum disorders: the case of synapsins. Front Pediatr 2:94

    PubMed  PubMed Central  Google Scholar 

  13. Schmunk G, Gargus JJ (2013) Channelopathy pathogenesis in autism spectrum disorders. Front Genet 4:222

    Article  PubMed  PubMed Central  Google Scholar 

  14. Stessman HA, Xiong B, Coe BP, Wang T, Hoekzema K, Fenckova M et al (2017) Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Nat Genet 49(4):515–526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kawamoto EM, Vivar C, Camandola S (2012) Physiology and pathology of calcium signaling in the brain. Front Pharmacol 3:61

    Article  PubMed  PubMed Central  Google Scholar 

  16. Arruda AP, Hotamisligil GS (2015) Calcium homeostasis and organelle function in the pathogenesis of obesity and diabetes. Cell Metab 22(3):381–397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Nguyen RL, Medvedeva YV, Ayyagari TE, Schmunk G, Gargus JJ (2018) Intracellular calcium dysregulation in autism spectrum disorder: an analysis of converging organelle signaling pathways. Biochim Biophys Acta (BBA) Mol Cell Res 1865(11):1718–1732

    Article  CAS  Google Scholar 

  18. Banderali U, Jain M, Thakur S, Jayanthan A, Belke DD, Giles WR et al (2022) The T-type calcium channel Cav3.1 in Y79 retinoblastoma cells is regulated by the epidermal growth factor receptor via the MAPK signaling pathway. Curr Eye Res 47(3):426–435

    Article  CAS  PubMed  Google Scholar 

  19. Hutchins BI, Li L, Kalil K (2012) Wnt-induced calcium signaling mediates axon growth and guidance in the developing corpus callosum. Sci Signal 5(206):pt1

    PubMed  Google Scholar 

  20. Boczek T, Radzik T, Ferenc B, Zylinska L (2019) The puzzling role of neuron-specific PMCA isoforms in the aging process. Int J Mol Sci 20(24):6338. https://doi.org/10.3390/ijms20246338

    Article  CAS  PubMed Central  Google Scholar 

  21. Alves VS, Alves-Silva HS, Orts DJB, Ribeiro-Silva L, Arcisio-Miranda M, Oliveira FA (2019) Calcium signaling in neurons and glial cells: role of Cav1 channels. Neuroscience 21(421):95–111

    Article  Google Scholar 

  22. Carafoli E, Krebs J (2016) Why calcium? How calcium became the best communicator. J Biol Chem 291(40):20849–20857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Puri BK (2020) Calcium signaling and gene expression. Adv Exp Med Biol 1131:537–545

    Article  CAS  PubMed  Google Scholar 

  24. Inoue T, Kato K, Kohda K, Mikoshiba K (1998) Type 1 inositol 1, 4, 5-trisphosphate receptor is required for induction of long-term depression in cerebellar Purkinje neurons. J Neurosci 18(14):5366–5373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hernández-López S, Tkatch T, Perez-Garci E, Galarraga E, Bargas J, Hamm H et al (2000) D2 dopamine receptors in striatal medium spiny neurons reduce L-type Ca2+ currents and excitability via a novel PLCβ1–IP3–calcineurin-signaling cascade. J Neurosci 20(24):8987–8995

    Article  PubMed  PubMed Central  Google Scholar 

  26. Li Y-X, Zhang Y, Lester HA, Schuman EM, Davidson N (1998) Enhancement of neurotransmitter release induced by brain-derived neurotrophic factor in cultured hippocampal neurons. J Neurosci 18(24):10231–10240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Gomez TM, Spitzer NC (1999) In vivo regulation of axon extension and pathfinding by growth-cone calcium transients. Nature 397(6717):350–355

    Article  CAS  PubMed  Google Scholar 

  28. Stutzmann GE, Caccamo A, LaFerla FM, Parker I (2004) Dysregulated IP3 signaling in cortical neurons of knock-in mice expressing an Alzheimer’s-linked mutation in presenilin1 results in exaggerated Ca2+ signals and altered membrane excitability. J Neurosci 24(2):508–513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gargus JJ (2003) Unraveling monogenic channelopathies and their implications for complex polygenic disease. Am J Hum Genet 72(4):785–803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bohnen M, Peng G, Robey S, Terrenoire C, Iyer V, Sampson K et al (2017) Molecular pathophysiology of congenital long QT syndrome. Physiol Rev 97(1):89–134

    Article  CAS  PubMed  Google Scholar 

  31. Rodan LH, Spillmann RC, Kurata HT, Lamothe SM, Maghera J, Jamra RA et al (2021) Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations. Genet Med 23(10):1922–1932

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Smedler E, Louhivuori L, Romanov RA, Masini D, Dehnisch Ellström I, Wang C et al (2022) Disrupted Cacna1c gene expression perturbs spontaneous Ca(2+) activity causing abnormal brain development and increased anxiety. Proc Natl Acad Sci USA. https://doi.org/10.1073/pnas.2108768119

    Article  PubMed  PubMed Central  Google Scholar 

  33. Campiglio M, Flucher BE (2015) The role of auxiliary subunits for the functional diversity of voltage-gated calcium channels. J Cell Physiol 230(9):2019–2031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Schmunk G, Boubion B, Smith I, Parker I, Gargus J (2015) Shared functional defect in IP3R-mediated calcium signaling in diverse monogenic autism syndromes. Transl Psychiatry 5(9):e643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Schmunk G, Nguyen RL, Ferguson DL, Kumar K, Parker I, Gargus JJ (2017) High-throughput screen detects calcium signaling dysfunction in typical sporadic autism spectrum disorder. Sci Rep 7(1):1–9

    Article  Google Scholar 

  36. Consortium C-DGotPG (2013) Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet 381(9875):1371–1379

    Article  Google Scholar 

  37. Gandal MJ, Haney JR, Parikshak NN, Leppa V, Ramaswami G, Hartl C et al (2018) Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap. Science 359(6376):693–697

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Vinkhuyzen AA, Eyles DW, Burne TH, Blanken LM, Kruithof CJ, Verhulst F et al (2017) Gestational vitamin D deficiency and autism spectrum disorder. BJPsych Open 3(2):85–90

    Article  PubMed  PubMed Central  Google Scholar 

  39. Fleet JC (2017) The role of vitamin D in the endocrinology controlling calcium homeostasis. Mol Cell Endocrinol 453:36–45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Liao X, Li Y (2020) Genetic associations between voltage-gated calcium channels and autism spectrum disorder: a systematic review. Mol Brain 13(1):96

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Soueid J, Kourtian S, Makhoul NJ, Makoukji J, Haddad S, Ghanem SS et al (2016) RYR2, PTDSS1 and AREG genes are implicated in a Lebanese population-based study of copy number variation in autism. Sci Rep 6(1):1–11

    Article  Google Scholar 

  42. Ambalavanan A, Girard SL, Ahn K, Zhou S, Dionne-Laporte A, Spiegelman D et al (2016) De novo variants in sporadic cases of childhood onset schizophrenia. Eur J Hum Genet 24(6):944–948

    Article  PubMed  Google Scholar 

  43. Balschun D, Wolfer DP, Bertocchini F, Barone V, Conti A, Zuschratter W et al (1999) Deletion of the ryanodine receptor type 3 (RyR3) impairs forms of synaptic plasticity and spatial learning. EMBO J 18(19):5264–5273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Tochigi M, Kato C, Ohashi J, Koishi S, Kawakubo Y, Yamamoto K et al (2008) No association between the ryanodine receptor 3 gene and autism in a Japanese population. Psychiatry Clin Neurosci 62(3):341–344

    Article  PubMed  Google Scholar 

  45. Prandini P, Pasquali A, Malerba G, Marostica A, Zusi C, Xumerle L et al (2012) The association of rs4307059 and rs35678 markers with autism spectrum disorders is replicated in Italian families. Psychiatr Genet 22(4):177–181

    Article  CAS  PubMed  Google Scholar 

  46. Takata A, Miyake N, Tsurusaki Y, Fukai R, Miyatake S, Koshimizu E et al (2018) Integrative analyses of de novo mutations provide deeper biological insights into autism spectrum disorder. Cell Rep 22(3):734–747

    Article  CAS  PubMed  Google Scholar 

  47. Ramoz N, Reichert JG, Smith CJ, Silverman JM, Bespalova IN, Davis KL et al (2004) Linkage and association of the mitochondrial aspartate/glutamate carrier SLC25A12 gene with autism. Am J Psychiatry 161(4):662–669

    Article  PubMed  Google Scholar 

  48. Kim H-G, Kishikawa S, Higgins AW, Seong I-S, Donovan DJ, Shen Y et al (2008) Disruption of neurexin 1 associated with autism spectrum disorder. Am J Hum Genet 82(1):199–207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kirov G, Gumus D, Chen W, Norton N, Georgieva L, Sari M et al (2008) Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia. Hum Mol Genet 17(3):458–465

    Article  CAS  PubMed  Google Scholar 

  50. Ching MS, Shen Y, Tan WH, Jeste SS, Morrow EM, Chen X et al (2010) Deletions of NRXN1 (neurexin-1) predispose to a wide spectrum of developmental disorders. Am J Med Genet B Neuropsychiatr Genet 153(4):937–947

    Google Scholar 

  51. Gregor A, Albrecht B, Bader I, Bijlsma EK, Ekici AB, Engels H et al (2011) Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1. BMC Med Genet 12(1):1–12

    Article  Google Scholar 

  52. Harrison V, Connell L, Hayesmoore J, McParland J, Pike MG, Blair E (2011) Compound heterozygous deletion of NRXN1 causing severe developmental delay with early onset epilepsy in two sisters. Am J Med Genet A 155(11):2826–2831

    Article  CAS  Google Scholar 

  53. Avazzadeh S, McDonagh K, Reilly J, Wang Y, Boomkamp SD, McInerney V et al (2019) Increased Ca2+ signaling in NRXN1α+/− neurons derived from ASD induced pluripotent stem cells. Mol Autism 10(1):1–16

    Article  Google Scholar 

  54. Vives L, Girirajan S, Karakoc E, Krumm N, Coe B, Levy R et al (2012) Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485(7397):246–250

    Article  PubMed  PubMed Central  Google Scholar 

  55. Girirajan S, Dennis MY, Baker C, Malig M, Coe BP, Campbell CD et al (2013) Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder. Am J Hum Genet 92(2):221–237

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Wang H, Yin F, Gao J, Fan X (2019) Association between 5-HTTLPR polymorphism and the risk of autism: a meta-analysis based on case-control studies. Front Psychiatry 10:51

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Hofer NT, Tuluc P, Ortner NJ, Nikonishyna YV, Fernándes-Quintero ML, Liedl KR et al (2020) Biophysical classification of a CACNA1D de novo mutation as a high-risk mutation for a severe neurodevelopmental disorder. Mol Autism 11(1):4

    Article  PubMed  PubMed Central  Google Scholar 

  58. Liaqat K, Schrauwen I, Raza SI, Lee K, Hussain S, Chakchouk I et al (2019) Identification of CACNA1D variants associated with sinoatrial node dysfunction and deafness in additional Pakistani families reveals a clinical significance. J Hum Genet 64(2):153–160

    Article  CAS  PubMed  Google Scholar 

  59. Souza IA, Gandini MA, Zamponi GW (2021) Splice-variant specific effects of a CACNA1H mutation associated with writer’s cramp. Mol Brain 14(1):145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Ficelova V, Souza IA, Cmarko L, Gandini MA, Stringer RN, Zamponi GW et al (2020) Functional identification of potential non-canonical N-glycosylation sites within Ca(v)3.2 T-type calcium channels. Mol Brain 13(1):149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Leahy KE, Wright T, Grudzinska Pechhacker MK, Audo I, Tumber A, Tavares E et al (2021) Optic atrophy and inner retinal thinning in CACNA1F-related congenital stationary night blindness. Genes (Basel) 12(3):330

    Article  CAS  Google Scholar 

  62. Williams B, Lopez JA, Maddox JW, Lee A (2020) Functional impact of a congenital stationary night blindness type 2 mutation depends on subunit composition of Ca(v)1.4 Ca(2+) channels. J Biol Chem 295(50):17215–17226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Sanchez-Sandoval AL, Herrera Carrillo Z, Díaz Velásquez CE, Delgadillo DM, Rivera HM, Gomora JC (2018) Contribution of S4 segments and S4–S5 linkers to the low-voltage activation properties of T-type CaV3.3 channels. PLoS ONE 13(2):e0193490

    Article  PubMed  PubMed Central  Google Scholar 

  64. Wang J, Zhang Y, Liang J, Pan H, Wu H, Xu K et al (2006) CACNA1I is not associated with childhood absence epilepsy in the Chinese Han population. Pediatr Neurol 35(3):187–190

    Article  PubMed  Google Scholar 

  65. Schneider T, Neumaier F, Hescheler J, Alpdogan S (2020) Cav2.3 R-type calcium channels: from its discovery to pathogenic de novo CACNA1E variants: a historical perspective. Pflugers Arch 472(7):811–816

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Kurokawa M, Torio M, Ohkubo K, Tocan V, Ohyama N, Toda N et al (2020) The expanding phenotype of hypokalemic periodic paralysis in a Japanese family with p.Val876Glu mutation in CACNA1S. Mol Genet Genomic Med 8(4):e1175

    Article  PubMed  PubMed Central  Google Scholar 

  67. Fernández-Quintero ML, El Ghaleb Y, Tuluc P, Campiglio M, Liedl KR, Flucher BE (2021) Structural determinants of voltage-gating properties in calcium channels. Elife. https://doi.org/10.7554/eLife.64087

    Article  PubMed  PubMed Central  Google Scholar 

  68. Chen J, Tan J, Greenshaw AJ, Sawalha J, Liu Y, Zhang X et al (2020) CACNB2 rs11013860 polymorphism correlates of prefrontal cortex thickness in bipolar patients with first-episode mania. J Affect Disord 268:82–87

    Article  CAS  PubMed  Google Scholar 

  69. Despang P, Salamon S, Breitenkamp AF, Kuzmenkina E, Herzig S, Matthes J (2020) Autism-associated mutations in the Ca(V)β(2) calcium-channel subunit increase Ba(2+)-currents and lead to differential modulation by the RGK-protein Gem. Neurobiol Dis 136:104721

    Article  CAS  PubMed  Google Scholar 

  70. Kong X, Li M, Shao K, Yang Y, Wang Q, Cai M (2020) Progesterone induces cell apoptosis via the CACNA2D3/Ca2+/p38 MAPK pathway in endometrial cancer. Oncol Rep 43(1):121–132

    CAS  PubMed  Google Scholar 

  71. Smedler E, Bergen SE, Song J, Landén M (2019) Genes, biomarkers, and clinical features associated with the course of bipolar disorder. Eur Neuropsychopharmacol 29(10):1152–1160

    Article  CAS  PubMed  Google Scholar 

  72. Warnier M, Roudbaraki M, Derouiche S, Delcourt P, Bokhobza A, Prevarskaya N et al (2015) CACNA2D2 promotes tumorigenesis by stimulating cell proliferation and angiogenesis. Oncogene 34(42):5383–5394

    Article  CAS  PubMed  Google Scholar 

  73. Antunes G, Roque AC, Simoes de Souza FM (2016) Modelling intracellular competition for calcium: kinetic and thermodynamic control of different molecular modes of signal decoding. Sci Rep 6(1):1–12

    Article  Google Scholar 

  74. Van Den Bossche MJ, Strazisar M, De Bruyne S, Bervoets C, Lenaerts AS, De Zutter S et al (2012) Identification of a CACNA2D4 deletion in late onset bipolar disorder patients and implications for the involvement of voltage-dependent calcium channels in psychiatric disorders. Am J Med Genet B Neuropsychiatr Genet 159(4):465–475

    Article  Google Scholar 

  75. Miranda A, Shekhtman T, McCarthy M, DeModena A, Leckband SG, Kelsoe JR (2019) Study of 45 candidate genes suggests CACNG2 may be associated with lithium response in bipolar disorder. J Affect Disord 248:175–179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. MacLean DM, Ramaswamy SS, Du M, Howe JR, Jayaraman V (2014) Stargazin promotes closure of the AMPA receptor ligand-binding domain. J Gen Physiol 144(6):503–512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Gambardella J, Jankauskas SS, D’Ascia SL, Sardu C, Matarese A, Minicucci F et al (2022) Glycation of ryanodine receptor in circulating lymphocytes predicts the response to cardiac resynchronization therapy. J Heart Lung Transplant 41(4):438–441

    Article  PubMed  Google Scholar 

  78. Shillington A, Zea Vera A, Perry T, Hopkin R, Thomas C, Cooper D et al (2021) Clinical RNA sequencing confirms compound heterozygous intronic variants in RYR1 in a patient with congenital myopathy, respiratory failure, neonatal brain hemorrhage, and d-transposition of the great arteries. Mol Genet Genomic Med 9(10):e1804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Roston TM, Wei J, Guo W, Li Y, Zhong X, Wang R et al (2022) Clinical and functional characterization of ryanodine receptor 2 variants implicated in calcium-release deficiency syndrome. JAMA Cardiol 7(1):84–92

    Article  PubMed  Google Scholar 

  80. Fernández-Morales J-C, Xia Y, Renzo TJ, Zhang X-H, Morad M (2022) Mutation in RyR2-FKBP binding site alters Ca2+ signaling modestly but increases “arrhythmogenesis” in human stem cells derived cardiomyocytes. Cell Calcium 101:102500

    Article  PubMed  Google Scholar 

  81. Gong S, Su BB, Tovar H, Mao C, Gonzalez V, Liu Y et al (2018) Polymorphisms within RYR3 gene are associated with risk and age at onset of hypertension, diabetes, and Alzheimer’s disease. Am J Hypertens 31(7):818–826

    Article  CAS  PubMed  Google Scholar 

  82. Chang Y-C, Chiu Y-F, He C-T, Sheu WH-H, Lin M-W, Seto TB et al (2016) Genome-wide linkage analysis and regional fine mapping identified variants in the RYR3 gene as a novel quantitative trait locus for circulating adiponectin in Chinese population. Medicine 95(44):e5174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Smits JJ, Oostrik J, Beynon AJ, Kant SG, de Koning Gans PAM, Rotteveel LJC et al (2019) De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment. Hum Genet 138(1):61–72

    Article  CAS  PubMed  Google Scholar 

  84. Vicario M, Zanni G, Vallese F, Santorelli F, Grinzato A, Cieri D et al (2018) A V1143F mutation in the neuronal-enriched isoform 2 of the PMCA pump is linked with ataxia. Neurobiol Dis 115:157–166

    Article  CAS  PubMed  Google Scholar 

  85. Xiong J, Wang N, Zhong HJ, Cui BW, Cheng S, Sun R et al (2021) SLC1A1 mediated glutamine addiction and contributed to natural killer T-cell lymphoma progression with immunotherapeutic potential. EBioMedicine 72:103614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Higashi Y, Aratake T, Shimizu S, Shimizu T, Saito M (2021) The neuroprotective role of EAAC1 in hippocampal injury following ischemia-reperfusion. Nihon Yakurigaku Zasshi 156(1):21–25

    Article  CAS  PubMed  Google Scholar 

  87. Liu J, Yang A, Zhang Q, Yang G, Yang W, Lei H et al (2015) Association between genetic variants in SLC25A12 and risk of autism spectrum disorders: an integrated meta-analysis. Am J Med Genet B Neuropsychiatr Genet 168b(4):236–246

    Article  PubMed  Google Scholar 

  88. Aoki Y, Cortese S (2016) Mitochondrial aspartate/glutamate carrier SLC25A12 and autism spectrum disorder: a meta-analysis. Mol Neurobiol 53(3):1579–1588

    Article  CAS  PubMed  Google Scholar 

  89. Nazzari S, Reali P, Ceppi E, Giorda R, Piazza C, Bianchi AM et al (2022) Respiratory sinus arrhythmia (RSA) stress response in preschool age varies by serotonin transporter polymorphism (5-HTTLPR): a preliminary report. J Exp Child Psychol 219:105413

    Article  PubMed  Google Scholar 

  90. Liu L, Hu Y, Lu Y, Hu L, Gao C, Nie S (2022) Sex-dependent DNA hypermethylation of SLC6A4 in patients with schizophrenia. Neurosci Lett 769:136394

    Article  CAS  PubMed  Google Scholar 

  91. Piccirillo S, Castaldo P, Macrì ML, Amoroso S, Magi S (2018) Glutamate as a potential “survival factor” in an in vitro model of neuronal hypoxia/reoxygenation injury: leading role of the Na(+)/Ca(2+) exchanger. Cell Death Dis 9(7):731

    Article  PubMed  PubMed Central  Google Scholar 

  92. Zhao F, Austria Q, Wang W, Zhu X (2021) Mfn2 overexpression attenuates MPTP neurotoxicity in vivo. Int J Mol Sci 22(2):601

    Article  CAS  PubMed Central  Google Scholar 

  93. Sun D, Zhu H, Ai L, Wu H, Wu Y, Jin J (2021) Mitochondrial fusion protein 2 regulates endoplasmic reticulum stress in preeclampsia. J Zhejiang Univ Sci B 22(2):165–170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Wu F, Quinonez M, Cannon SC (2021) Gating pore currents occur in CaV1.1 domain III mutants associated with HypoPP. J Gen Physiol. https://doi.org/10.1085/jgp.202112946

    Article  PubMed  PubMed Central  Google Scholar 

  95. Jubran R, Saar-Ray M, Wawruszak A, Ziporen L, Donin N, Bairey O et al (2020) Mortalin peptides exert antitumor activities and act as adjuvants to antibody-mediated complement-dependent cytotoxicity. Int J Oncol 57(4):1013–1026

    CAS  PubMed  Google Scholar 

  96. Zheng S, Wu R, Deng Y, Zhang Q (2022) Dihydroartemisinin represses oral squamous cell carcinoma progression through downregulating mitochondrial calcium uniporter. Bioengineered 13(1):227–241

    Article  CAS  PubMed  Google Scholar 

  97. Foskett JK (2020) Uncorking MCU to let the calcium flow. Cell Calcium 91:102257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Gottschalk B, Klec C, Leitinger G, Bernhart E, Rost R, Bischof H et al (2019) MICU1 controls cristae junction and spatially anchors mitochondrial Ca(2+) uniporter complex. Nat Commun 10(1):3732

    Article  PubMed  PubMed Central  Google Scholar 

  99. Bhosale G, Sharpe JA, Koh A, Kouli A, Szabadkai G, Duchen MR (2017) Pathological consequences of MICU1 mutations on mitochondrial calcium signalling and bioenergetics. Biochim Biophys Acta Mol Cell Res 1864(6):1009–1017

    Article  CAS  PubMed  Google Scholar 

  100. Shamseldin HE, Alasmari A, Salih MA, Samman MM, Mian SA, Alshidi T et al (2017) A null mutation in MICU2 causes abnormal mitochondrial calcium homeostasis and a severe neurodevelopmental disorder. Brain 140(11):2806–2813

    Article  PubMed  Google Scholar 

  101. Bick AG, Wakimoto H, Kamer KJ, Sancak Y, Goldberger O, Axelsson A et al (2017) Cardiovascular homeostasis dependence on MICU2, a regulatory subunit of the mitochondrial calcium uniporter. Proc Natl Acad Sci USA 114(43):E9096–E9104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Bonora E, Graziano C, Minopoli F, Bacchelli E, Magini P, Diquigiovanni C et al (2014) Maternally inherited genetic variants of CADPS2 are present in autism spectrum disorders and intellectual disability patients. EMBO Mol Med 6(6):795–809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Okamoto N, Hatsukawa Y, Shimojima K, Yamamoto T (2011) Submicroscopic deletion in 7q31 encompassing CADPS2 and TSPAN12 in a child with autism spectrum disorder and PHPV. Am J Med Genet A 155a(7):1568–1573

    Article  PubMed  Google Scholar 

  104. Auclair J, Busine MP, Navarro C, Ruano E, Montmain G, Desseigne F et al (2006) Systematic mRNA analysis for the effect of MLH1 and MSH2 missense and silent mutations on aberrant splicing. Hum Mutat 27(2):145–154

    Article  CAS  PubMed  Google Scholar 

  105. Dominguez-Valentin M, Plazzer JP, Sampson JR, Engel C, Aretz S, Jenkins MA et al (2021) No difference in penetrance between truncating and missense/aberrant splicing pathogenic variants in MLH1 and MSH2: a prospective lynch syndrome database study. J Clin Med 10(13):2856

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Ma C, Li X, Chen J, Li Z, Guan J, Li Y et al (2020) Association analysis between common variants of the TRPM1 gene and three mental disorders in the Han Chinese population. Genet Test Mol Biomark 24(10):649–657

    Article  CAS  Google Scholar 

  107. Kim MS, Hong HK, Ko YJ, Park KH, Ueno S, Okado S et al (2020) A case of melanoma-associated retinopathy with autoantibodies against TRPM1. Doc Ophthalmol 141(3):313–318

    Article  PubMed  Google Scholar 

  108. Zhang Y, Maitikuerban B, Chen Y, Li Y, Cao Y, Xu X (2021) Correlation between classical transient receptor potential channel 1 gene polymorphism and microalbuminuria in patients with primary hypertension. Clin Exp Hypertens 43(5):443–449

    Article  CAS  PubMed  Google Scholar 

  109. Farfariello V, Gordienko DV, Mesilmany L, Touil Y, Germain E, Fliniaux I et al (2022) TRPC3 shapes the ER-mitochondria Ca(2+) transfer characterizing tumour-promoting senescence. Nat Commun 13(1):956

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Boyle CA, Hu B, Quaintance KL, Lei S (2021) Involvement of TRPC5 channels, inwardly rectifying K(+) channels, PLCβ and PIP(2) in vasopressin-mediated excitation of medial central amygdala neurons. J Physiol 599(12):3101–3119

    Article  CAS  PubMed  Google Scholar 

  111. Ningoo M, Plant LD, Greka A, Logothetis DE (2021) PIP(2) regulation of TRPC5 channel activation and desensitization. J Biol Chem 296:100726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Poduslo SE, Huang R, Huang J, Smith S (2009) Genome screen of late-onset Alzheimer’s extended pedigrees identifies TRPC4AP by haplotype analysis. Am J Med Genet B Neuropsychiatr Genet 150b(1):50–55

    Article  CAS  PubMed  Google Scholar 

  113. Peng JM, Tseng RH, Shih TC, Hsieh SY (2021) CAMK2N1 suppresses hepatoma growth through inhibiting E2F1-mediated cell-cycle signaling. Cancer Lett 497:66–76

    Article  CAS  PubMed  Google Scholar 

  114. Karandur D, Bhattacharyya M, Xia Z, Lee YK, Muratcioglu S, McAffee D et al (2020) Breakage of the oligomeric CaMKII hub by the regulatory segment of the kinase. Elife. https://doi.org/10.7554/eLife.57784

    Article  PubMed  PubMed Central  Google Scholar 

  115. Thornquist SC, Langer K, Zhang SX, Rogulja D, Crickmore MA (2020) CaMKII measures the passage of time to coordinate behavior and motivational state. Neuron 105(2):334–45.e9

    Article  CAS  PubMed  Google Scholar 

  116. Liu H, Wang L, Dai L, Feng F, Xiao Y (2021) CaMK II/Ca2+ dependent endoplasmic reticulum stress mediates apoptosis of hepatic stellate cells stimulated by transforming growth factor beta 1. Int J Biol Macromol 172:321–329

    Article  CAS  PubMed  Google Scholar 

  117. Roy JP, Halford MM, Stacker SA (2018) The biochemistry, signalling and disease relevance of RYK and other WNT-binding receptor tyrosine kinases. Growth Factors 36(1–2):15–40

    Article  CAS  PubMed  Google Scholar 

  118. Giménez-Bastida JA, González-Sarrías A, Laparra-Llopis JM, Schneider C, Espín JC (2021) Targeting mammalian 5-lipoxygenase by dietary phenolics as an anti-inflammatory mechanism: a systematic review. Int J Mol Sci 22(15):7937

    Article  PubMed  PubMed Central  Google Scholar 

  119. Voros O, Panyi G, Hajdu P (2021) Immune synapse residency of orai1 alters Ca(2+) response of T cells. Int J Mol Sci 22(21):11514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Wang CH, Liang WC, Lin PC, Jong YJ (2022) Combination of thrombocytopenia and hypocalcemia may indicate the possibility of Stormorken syndrome with STIM1 mutation. Pediatr Neonatol 63(2):198–199

    Article  PubMed  Google Scholar 

  121. He T, Lnenicka GA (2011) Ca2+ buffering at a drosophila larval synaptic terminal. Synapse 65(7):687–693

    Article  CAS  PubMed  Google Scholar 

  122. Schepelmann M, Kupper N, Sladczyk M, Mansfield B, Manhardt T, Piatek K et al (2021) Stereo-specific modulation of the extracellular calcium-sensing receptor in colon cancer cells. Int J Mol Sci 22(18):10124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Ngamkam J, Vadcharavivad S, Areepium N, Auamnoy T, Takkavatakarn K, Katavetin P et al (2021) The impact of CASR A990G polymorphism in response to cinacalcet treatment in hemodialysis patients with secondary hyperparathyroidism. Sci Rep 11(1):18006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Shoshan-Barmatz V, Shteinfer-Kuzmine A, Verma A (2020) VDAC1 at the intersection of cell metabolism, apoptosis, and diseases. Biomolecules 10(11):1485

    Article  CAS  PubMed Central  Google Scholar 

  125. Wang B, Zou L, Zhou L (2021) Lipid bilayers regulate allosteric signal of NMDA receptor GluN1 C-terminal domain. Biochem Biophys Res Commun 585:15–21

    Article  CAS  PubMed  Google Scholar 

  126. Reilly J, Gallagher L, Leader G, Shen S (2020) Coupling of autism genes to tissue-wide expression and dysfunction of synapse, calcium signalling and transcriptional regulation. PLoS ONE 15(12):e0242773

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Raynal NJ, Lee JT, Wang Y, Beaudry A, Madireddi P, Garriga J et al (2016) Targeting calcium signaling induces epigenetic reactivation of tumor suppressor genes in cancer. Cancer Res 76(6):1494–1505

    Article  CAS  PubMed  Google Scholar 

  128. Wang Q, Kong Y, Wu D-Y, Liu J-H, Jie W, You Q-L et al (2021) Impaired calcium signaling in astrocytes modulates autism spectrum disorder-like behaviors in mice. Nat Commun 12(1):1–13

    Google Scholar 

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Acknowledgements

The current study was supported by a grant from Shahid Beheshti University of Medical Sciences.

Funding

The current study was supported by a grant from Shahid Beheshti University of Medical Sciences.

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  1. Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Ashkan Pourtavakoli & Soudeh Ghafouri-Fard

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  1. Ashkan Pourtavakoli
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  2. Soudeh Ghafouri-Fard
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SG-F wrote the manuscript. AP designed tables and figure. All authors read and approved the submitted version.

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Correspondence to Soudeh Ghafouri-Fard.

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The study protocol was approved by ethical committee of Shahid Beheshti University of Medical Sciences. All procedures performed were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Pourtavakoli, A., Ghafouri-Fard, S. Calcium signaling in neurodevelopment and pathophysiology of autism spectrum disorders. Mol Biol Rep 49, 10811–10823 (2022). https://doi.org/10.1007/s11033-022-07775-6

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