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L-Type Calcium Channels Modulation by Estradiol

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Abstract

Voltage-gated calcium channels are key regulators of brain function, and their dysfunction has been associated with multiple conditions and neurodegenerative diseases because they couple membrane depolarization to the influx of calcium—and other processes such as gene expression—in excitable cells. L-type calcium channels, one of the three major classes and probably the best characterized of the voltage-gated calcium channels, act as an essential calcium binding proteins with a significant biological relevance. It is well known that estradiol can activate rapidly brain signaling pathways and modulatory/regulatory proteins through non-genomic (or non-transcriptional) mechanisms, which lead to an increase of intracellular calcium that activate multiple kinases and signaling cascades, in the same way as L-type calcium channels responses. In this context, estrogens—L-type calcium channels signaling raises intracellular calcium levels and activates the same signaling cascades in the brain probably through estrogen receptor-independent modulatory mechanisms. In this review, we discuss the available literature on this area, which seems to suggest that estradiol exerts dual effects/modulation on these channels in a concentration-dependent manner (as a potentiator of these channels in pM concentrations and as an inhibitor in nM concentrations). Indeed, estradiol may orchestrate multiple neurotrophic responses, which open a new avenue for the development of novel estrogen-based therapies to alleviate different neuropathologies. We also highlight that it is essential to determine through computational and/or experimental approaches the interaction between estradiol and L-type calcium channels to assist these developments, which is an interesting area of research that deserves a closer look in future biomedical research.

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References

  1. Yang X-P, Reckelhoff JF (2011) Estrogen, hormonal replacement therapy and cardiovascular disease. Curr Opin Nephrol Hypertens 20:133–138. doi:10.1097/MNH.0b013e3283431921

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Dye RV, Miller KJ, Singer EJ, Levine AJ (2012) Hormone replacement therapy and risk for neurodegenerative diseases. Int J Alzheimers Dis 2012:1–18. doi:10.1155/2012/258454

    Article  CAS  Google Scholar 

  3. Hodis HN, Mack WJ (2014) Hormone replacement therapy and the association with coronary heart disease and overall mortality: clinical application of the timing hypothesis. J Steroid Biochem Mol Biol 142:68–75. doi:10.1016/j.jsbmb.2013.06.011

    Article  CAS  PubMed  Google Scholar 

  4. Luine VN (2014) Estradiol and cognitive function: past, present and future. Horm Behav 66:602–618. doi:10.1016/j.yhbeh.2014.08.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ticconi C, Pietropolli A, Piccione E (2013) Estrogen replacement therapy and asthma. Pulm Pharmacol Ther 26:617–623. doi:10.1016/j.pupt.2013.08.004

    Article  CAS  PubMed  Google Scholar 

  6. Brinton RD (2004) Impact of estrogen therapy on Alzheimer’s disease: a fork in the road? CNS Drugs 18:405–422. doi:10.2165/00023210-200418070-00001

    Article  CAS  PubMed  Google Scholar 

  7. Ingle JN (2002) Estrogen as therapy for breast cancer. Breast Cancer Res 4:133–136. doi:10.1186/bcr436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Nelles JL, Hu W-Y, Prins GS (2011) Estrogen action and prostate cancer. Expert Rev Endocrinol Metab 6:437–451. doi:10.1586/eem.11.20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Oh WK (2002) The evolving role of estrogen therapy in prostate cancer. Clin Prostate Cancer 1:81–89

    Article  CAS  PubMed  Google Scholar 

  10. Brown SB, Hankinson SE (2015) Endogenous estrogens and the risk of breast, endometrial, and ovarian cancers. Steroids 99:8–10. doi:10.1016/j.steroids.2014.12.013

    Article  CAS  PubMed  Google Scholar 

  11. Yue W, Yager JD, Wang J-P, et al. (2013) Estrogen receptor-dependent and independent mechanisms of breast cancer carcinogenesis. Steroids 78:161–170. doi:10.1016/j.steroids.2012.11.001

    Article  CAS  PubMed  Google Scholar 

  12. Savage L (2008) Estrogen therapy increases benign breast disease. JNCI J Natl Cancer Inst 100:519–519. doi:10.1093/jnci/djn137

    Google Scholar 

  13. Ellem SJ, Risbridger GP (2006) Aromatase and prostate cancer. Minerva Endocrinol 31:1–12

    CAS  PubMed  Google Scholar 

  14. Barreto GE (2011) Neuroprotection by estradiol: some important considerations. Hum Exp Toxicol 30:1737–1739. doi:10.1177/0960327111398676

    Article  CAS  PubMed  Google Scholar 

  15. Lopez-Rodriguez AB, Ávila-Rodriguez M, Vega-Vela NE, et al. (2015) Neuroprotection by exogenous estrogenic compounds following traumatic brain injury. In: Estrogen Eff. Trauma. Brain Inj. Elsevier, pp 73–90

  16. Garcia-Segura LM, Azcoitia I, DonCarlos LL (2001) Neuroprotection by estradiol. Prog Neurobiol 63:29–60

    Article  CAS  PubMed  Google Scholar 

  17. Arevalo M-A, Azcoitia I, Garcia-Segura LM (2015) The neuroprotective actions of oestradiol and oestrogen receptors. Nat Rev Neurosci 16:17–29. doi:10.1038/nrn3856

    Article  CAS  PubMed  Google Scholar 

  18. Garcia-Segura LM, Balthazart J (2009) Steroids and neuroprotection: new advances. Front Neuroendocrinol 30:v–ix. doi:10.1016/j.yfrne.2009.04.006

    Article  PubMed  PubMed Central  Google Scholar 

  19. Kulkarni J, Gavrilidis E, Worsley R, Hayes E (2012) Role of estrogen treatment in the management of schizophrenia. CNS Drugs 26:549–557. doi:10.2165/11630660-000000000-00000

    Article  CAS  PubMed  Google Scholar 

  20. Kulkarni J, Gavrilidis E, Worsley R, et al. (2013) The role of estrogen in the treatment of men with schizophrenia. Int J Endocrinol Metab. doi:10.5812/ijem.6615

    PubMed  PubMed Central  Google Scholar 

  21. Lanussa OH, Ávila-Rodriguez M, García-Segura LM, et al. (2016) Microglial dependent protective effects of neuroactive steroids. CNS Neurol. Disord. Drug Targets

  22. Barreto GE, Santos-Galindo M, Garcia-Segura LM (2014) Selective estrogen receptor modulators regulate reactive microglia after penetrating brain injury. Front Aging Neurosci 6:132. doi:10.3389/fnagi.2014.00132

    PubMed  PubMed Central  Google Scholar 

  23. Barreto G, Santos-Galindo M, Diz-Chaves Y, et al. (2009) Selective estrogen receptor modulators decrease reactive astrogliosis in the injured brain: effects of aging and prolonged depletion of ovarian hormones. Endocrinology 150:5010–5015. doi:10.1210/en.2009-0352

    Article  CAS  PubMed  Google Scholar 

  24. Barreto G, Veiga S, Azcoitia I, et al. (2007) Testosterone decreases reactive astroglia and reactive microglia after brain injury in male rats: role of its metabolites, oestradiol and dihydrotestosterone. Eur J Neurosci 25:3039–3046. doi:10.1111/j.1460-9568.2007.05563.x

    Article  PubMed  Google Scholar 

  25. Avila-Rodriguez M, Garcia-Segura LM, Cabezas R, et al. (2014) Tibolone protects T98G cells from glucose deprivation. J Steroid Biochem Mol Biol. doi:10.1016/j.jsbmb.2014.07.009

    PubMed  Google Scholar 

  26. Avila MF, Cabezas R, Torrente D, et al. (2013) Novel interactions of GRP78: UPR and estrogen responses in the brain. Cell Biol Int 37:521–532. doi:10.1002/cbin.10058

    Article  CAS  PubMed  Google Scholar 

  27. Giefing-Kröll C, Berger P, Lepperdinger G, Grubeck-Loebenstein B (2015) How sex and age affect immune responses, susceptibility to infections, and response to vaccination. Aging Cell 14:309–321. doi:10.1111/acel.12326

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Cui J, Shen Y, Li R (2013) Estrogen synthesis and signaling pathways during aging: from periphery to brain. Trends Mol Med 19:197–209. doi:10.1016/j.molmed.2012.12.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bird MD, Karavitis J, Kovacs EJ (2008) Sex differences and estrogen modulation of the cellular immune response after injury. Cell Immunol 252:57–67. doi:10.1016/j.cellimm.2007.09.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wend K, Wend P, Krum SA (2012) Tissue-specific effects of loss of estrogen during menopause and aging. Front Endocrinol (Lausanne). doi:10.3389/fendo.2012.00019

    Google Scholar 

  31. Gillies GE, McArthur S (2010) Estrogen actions in the brain and the basis for differential action in men and women: a case for sex-specific medicines. Pharmacol Rev 62:155–198. doi:10.1124/pr.109.002071

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Markou A, Duka T, Prelevic GM (2005) Estrogens and brain function. Hormones (Athens) 4:9–17

    Article  Google Scholar 

  33. Nilsson S, Mäkelä S, Treuter E, et al. (2001) Mechanisms of estrogen action. Physiol Rev 81:1535–1565

    CAS  PubMed  Google Scholar 

  34. Brann DW, Dhandapani K, Wakade C, et al. (2007) Neurotrophic and neuroprotective actions of estrogen: basic mechanisms and clinical implications. Steroids 72:381–405. doi:10.1016/j.steroids.2007.02.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Nelson LR, Bulun SE (2001) Estrogen production and action. J Am Acad Dermatol 45:S116–S124

    Article  CAS  PubMed  Google Scholar 

  36. McEwen B (2002) Estrogen actions throughout the brain. Recent Prog Horm Res 57:357–384

    Article  CAS  PubMed  Google Scholar 

  37. McEwen BS, Akama KT, Spencer-Segal JL, et al. (2012) Estrogen effects on the brain: actions beyond the hypothalamus via novel mechanisms. Behav Neurosci 126:4–16. doi:10.1037/a0026708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Tang MX, Jacobs D, Stern Y, et al. (1996) Effect of oestrogen during menopause on risk and age at onset of Alzheimer’s disease. Lancet (London, England) 348:429–432. doi:10.1016/S0140-6736(96)03356-9

    Article  CAS  Google Scholar 

  39. Shumaker SA, Legault C, Kuller L, et al. (2004) Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women’s Health Initiative Memory study. JAMA 291:2947–2958. doi:10.1001/jama.291.24.2947

    Article  CAS  PubMed  Google Scholar 

  40. Ha DM, Xu J, Janowsky JS (2007) Preliminary evidence that long-term estrogen use reduces white matter loss in aging. Neurobiol Aging 28:1936–1940. doi:10.1016/j.neurobiolaging.2006.08.007

    Article  CAS  PubMed  Google Scholar 

  41. Grimm A, Lim Y-A, Mensah-Nyagan AG, et al. (2012) Alzheimer’s disease, oestrogen and mitochondria: an ambiguous relationship. Mol Neurobiol 46:151–160. doi:10.1007/s12035-012-8281-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Simoncini T, Genazzani A (2003) Non-genomic actions of sex steroid hormones. Eur J Endocrinol 148:281–292. doi:10.1530/eje.0.1480281

    Article  CAS  PubMed  Google Scholar 

  43. Vasudevan N, Pfaff DW (2008) Non-genomic actions of estrogens and their interaction with genomic actions in the brain. Front Neuroendocrinol 29:238–257. doi:10.1016/j.yfrne.2007.08.003

    Article  CAS  PubMed  Google Scholar 

  44. Sak K, Everaus H (2004) Nongenomic effects of 17β-estradiol—diversity of membrane binding sites. J Steroid Biochem Mol Biol 88:323–335. doi:10.1016/j.jsbmb.2004.01.004

    Article  CAS  PubMed  Google Scholar 

  45. Ortner NJ, Striessnig J (2015) L-type calcium channels as drug targets in CNS disorders. Channels (Austin):1–7. doi:10.1080/19336950.2015.1048936

  46. Torrente D, Mendes-da-Silva RF, Lopes AAC, et al. (2014) Increased calcium influx triggers and accelerates cortical spreading depression in vivo in male adult rats. Neurosci Lett 558:87–90. doi:10.1016/j.neulet.2013.11.004

    Article  CAS  PubMed  Google Scholar 

  47. Charlier TD, Cornil CA, Ball GF, Balthazart J (2010) Diversity of mechanisms involved in aromatase regulation and estrogen action in the brain. Biochim Biophys Acta 1800:1094–1105. doi:10.1016/j.bbagen.2009.12.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kelly MJ, Rønnekleiv OK (2009) Control of CNS neuronal excitability by estrogens via membrane-initiated signaling. Mol Cell Endocrinol 308:17–25. doi:10.1016/j.mce.2009.03.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Sarkar SN, Huang R-Q, Logan SM, et al. (2008) Estrogens directly potentiate neuronal L-type Ca2+ channels. Proc Natl Acad Sci U S A 105:15148–15153. doi:10.1073/pnas.0802379105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Wu T-W, Wang JM, Chen S, Brinton RD (2005) 17Beta-estradiol induced Ca2+ influx via L-type calcium channels activates the Src/ERK/cyclic-AMP response element binding protein signal pathway and BCL-2 expression in rat hippocampal neurons: a potential initiation mechanism for estrogen-induced neurop. Neuroscience 135:59–72. doi:10.1016/j.neuroscience.2004.12.027

    Article  CAS  PubMed  Google Scholar 

  51. Berridge MJ, Lipp P, Bootman MD (2000) The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol 1:11–21. doi:10.1038/35036035

    Article  CAS  PubMed  Google Scholar 

  52. Carafoli E (2002) Calcium signaling: a tale for all seasons. Proc Natl Acad Sci 99:1115–1122. doi:10.1073/pnas.032427999

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Verkhratsky A, Landfield PW, Thibault O (2002) Ca2+ and neuronal pathology. Eur J Pharmacol 447:115–117

    Article  CAS  PubMed  Google Scholar 

  54. Berridge MJ, Bootman MD, Roderick HL (2003) Calcium: calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol 4:517–529. doi:10.1038/nrm1155

    Article  CAS  PubMed  Google Scholar 

  55. Reuter H (1983) Calcium channel modulation by neurotransmitters, enzymes and drugs. Nature 301:569–574. doi:10.1038/301569a0

    Article  CAS  PubMed  Google Scholar 

  56. Catterall W a (2000) Structure and regulation of voltage-gated Ca2+ channels. Annu Rev Cell Dev Biol 16:521–555. doi:10.1146/annurev.cellbio.16.1.521

    Article  CAS  PubMed  Google Scholar 

  57. Tsien RW, Tsien RY (1990) Calcium channels, stores, and oscillations. Annu Rev Cell Biol 6:715–760. doi:10.1146/annurev.cb.06.110190.003435

    Article  CAS  PubMed  Google Scholar 

  58. Lipscombe D (2004) L-type calcium channels: the low down. J Neurophysiol 92:2633–2641. doi:10.1152/jn.00486.2004

    Article  CAS  PubMed  Google Scholar 

  59. Torrente D, Cabezas R, Avila MF, et al. (2014) Cortical spreading depression in traumatic brain injuries: is there a role for astrocytes? Neurosci Lett 565:2–6. doi:10.1016/j.neulet.2013.12.058

    Article  CAS  PubMed  Google Scholar 

  60. Metea MR, Newman EA (2006) Calcium signaling in specialized glial cells. Glia 54:650–655. doi:10.1002/glia.20352

    Article  PubMed  PubMed Central  Google Scholar 

  61. Deitmer JWW, Verkhratsky AJJ, Lohr C (1998) Calcium signalling in glial cells. Cell Calcium 24:405–416. doi:10.1016/S0143-4160(98)90063-X

    Article  CAS  PubMed  Google Scholar 

  62. Verkhratsky A, Kettenmann H (1996) Calcium signalling in glial cells. Trends Neurosci 19:346–352

    Article  CAS  PubMed  Google Scholar 

  63. Cornell-Bell A, Finkbeiner S, Cooper M, Smith S (1990) Glutamate induces calcium waves in cultured astrocytes: long-range glial signaling. Science 247:470–473. doi:10.1126/science.1967852

    Article  CAS  PubMed  Google Scholar 

  64. Finkbeiner S (1992) Calcium waves in astrocytes—filling in the gaps. Neuron 8:1101–1108

    Article  CAS  PubMed  Google Scholar 

  65. Amédée T, Ellie E, Dupouy B, Vincent JD (1991) Voltage-dependent calcium and potassium channels in Schwann cells cultured from dorsal root ganglia of the mouse. J Physiol 441:35–56

    Article  PubMed  PubMed Central  Google Scholar 

  66. Barres BA, Chun LL, Corey DP (1989) Calcium current in cortical astrocytes: induction by cAMP and neurotransmitters and permissive effect of serum factors. J Neurosci 9:3169–3175

    CAS  PubMed  Google Scholar 

  67. Triggle D (1998) The physiological and pharmacological significance of cardiovascular T-type, voltage-gated calcium channels. Am J Hypertens 11:80S–87S. doi:10.1016/S0895-7061(98)00004-1

    Article  CAS  PubMed  Google Scholar 

  68. Obermair GJ, Tuluc P, Flucher BE (2008) Auxiliary Ca(2+) channel subunits: lessons learned from muscle. Curr Opin Pharmacol 8:311–318. doi:10.1016/j.coph.2008.01.008

    Article  CAS  PubMed  Google Scholar 

  69. Catterall WA (1991) Structure and function of voltage-gated sodium and calcium channels. Curr Opin Neurobiol 1:5–13

    Article  CAS  PubMed  Google Scholar 

  70. Casamassima F, Hay AC, Benedetti A, et al. (2010) L-type calcium channels and psychiatric disorders: a brief review. Am J Med Genet Part B Neuropsychiatr Genet 153B:1373–1390. doi:10.1002/ajmg.b.31122

    Article  CAS  Google Scholar 

  71. Nowycky MC, Fox AP, Tsien RW (1985) Three types of neuronal calcium channel with different calcium agonist sensitivity. Nature 316:440–443. doi:10.1038/316440a0

    Article  CAS  PubMed  Google Scholar 

  72. Ertel EA, Campbell KP, Harpold MM, et al. (2000) Nomenclature of voltage-gated calcium channels. Neuron 25:533–535

    Article  CAS  PubMed  Google Scholar 

  73. Lipscombe D (2002) L-type calcium channels: highs and new lows. Circ Res 90:933–935

    Article  CAS  PubMed  Google Scholar 

  74. Catterall WA, Swanson TM (2015) Structural basis for pharmacology of voltage-gated sodium and calcium channels. Mol Pharmacol 88:141–150. doi:10.1124/mol.114.097659

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Snutch TP, Reiner PB (1992) Ca2+ channels: diversity of form and function. Curr Opin Neurobiol 2:247–253. doi:10.1016/0959-4388(92)90111-W

    Article  CAS  PubMed  Google Scholar 

  76. Glasser SP (1998) The relevance of T-type calcium antagonists: a profile of mibefradil. J Clin Pharmacol 38:659–669

    Article  CAS  PubMed  Google Scholar 

  77. Ertel EA (2004) Pharmacology of Cav3 (T-Type) Channels. In: Calcium Channel Pharmacol. Springer US, Boston, MA, pp 183–236

  78. Sampson K, Kass R (2006) Anti-arrhythmic drugs. In: Brunton L (ed) Goodman Gilman’s Pharmacol. Basis Ther, 11th edn. McGraw-Hill, Inc., New York, pp. 815–848

    Google Scholar 

  79. Michel T, Hoffmann B (2011) Treatment of myocardial ischemia and hypertension. In: Goodman Gilman’s Pharmacol. Basis Ther. McGraw-Hill Co., New York, pp. 745–788

    Google Scholar 

  80. Lewis RJ, Dutertre S, Vetter I, Christie MJ (2012) Conus venom peptide pharmacology. Pharmacol Rev 64:259–298. doi:10.1124/pr.111.005322

    Article  CAS  PubMed  Google Scholar 

  81. Davies A, Hendrich J, Van Minh AT, et al. (2007) Functional biology of the alpha(2)delta subunits of voltage-gated calcium channels. Trends Pharmacol Sci 28:220–228. doi:10.1016/j.tips.2007.03.005

    Article  CAS  PubMed  Google Scholar 

  82. Catterall WA, Striessnig J (1992) Receptor sites for Ca2+ channel antagonists. Trends Pharmacol Sci 13:256–262

    Article  CAS  PubMed  Google Scholar 

  83. Hockerman GH, Peterson BZ, Sharp E, et al. (1997) Construction of a high-affinity receptor site for dihydropyridine agonists and antagonists by single amino acid substitutions in a non-L-type Ca2+ channel. Proc Natl Acad Sci U S A 94:14906–14911

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Ito H, Klugbauer N, Hofmann F (1997) Transfer of the high affinity dihydropyridine sensitivity from L-type to non-L-type calcium channel. Mol Pharmacol 52:735–740

    CAS  PubMed  Google Scholar 

  85. Sinnegger MJ, Wang Z, Grabner M, et al. (1997) Nine L-type amino acid residues confer full 1,4-dihydropyridine sensitivity to the neuronal calcium channel alpha1A subunit. Role of L-type Met1188. J Biol Chem 272:27686–27693

    Article  CAS  PubMed  Google Scholar 

  86. Tsien RWW, Lipscombe D, Madison DVV, et al. (1988) Multiple types of neuronal calcium channels and their selective modulation. Trends Neurosci 11:431–438. doi:10.1016/0166-2236(88)90194-4

    Article  CAS  PubMed  Google Scholar 

  87. Miller RJ (1987) Multiple calcium channels and neuronal function. Science 235:46–52

    Article  CAS  PubMed  Google Scholar 

  88. Hofmann F, Flockerzi V, Kahl S, Wegener JW (2014) L-type CaV1.2 calcium channels: from in vitro findings to in vivo function. Physiol Rev 94:303–326. doi:10.1152/physrev.00016.2013

    Article  CAS  PubMed  Google Scholar 

  89. Berger SM, Bartsch D (2014) The role of L-type voltage-gated calcium channels Cav1.2 and Cav1.3 in normal and pathological brain function. Cell Tissue Res 357:463–476. doi:10.1007/s00441-014-1936-3

    Article  CAS  PubMed  Google Scholar 

  90. Striessnig J, Pinggera A, Kaur G, et al. (2014) L-type Ca 2+ channels in heart and brain. Wiley Interdiscip Rev Membr Transp Signal 3:15–38. doi:10.1002/wmts.102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Gargus JJ (2006) Ion channel functional candidate genes in multigenic neuropsychiatric disease. Biol Psychiatry 60:177–185. doi:10.1016/j.biopsych.2005.12.008

    Article  CAS  PubMed  Google Scholar 

  92. Splawski I, Yoo DS, Stotz SC, et al. (2006) CACNA1H mutations in autism spectrum disorders. J Biol Chem 281:22085–22091. doi:10.1074/jbc.M603316200

    Article  CAS  PubMed  Google Scholar 

  93. Calin-Jageman I, Lee A (2008) Ca v 1 L-type Ca 2+ channel signaling complexes in neurons. J Neurochem 105:573–583. doi:10.1111/j.1471-4159.2008.05286.x

    Article  CAS  PubMed  Google Scholar 

  94. Hell JW, Westenbroek RE, Warner C, et al. (1993) Identification and differential subcellular localization of the neuronal class C and class D L-type calcium channel alpha 1 subunits. J Cell Biol 123:949–962

    Article  CAS  PubMed  Google Scholar 

  95. Westenbroek RE, Hoskins L, Catterall WA (1998) Localization of Ca2+ channel subtypes on rat spinal motor neurons, interneurons, and nerve terminals. J Neurosci 18:6319–6330

    CAS  PubMed  Google Scholar 

  96. Williams ME, Feldman DH, McCue AF, et al. (1992) Structure and functional expression of alpha 1, alpha 2, and beta subunits of a novel human neuronal calcium channel subtype. Neuron 8:71–84

    Article  CAS  PubMed  Google Scholar 

  97. Ludwig A, Flockerzi V, Hofmann F (1997) Regional expression and cellular localization of the alpha1 and beta subunit of high voltage-activated calcium channels in rat brain. J Neurosci 17:1339–1349

    CAS  PubMed  Google Scholar 

  98. Takimoto K, Li D, Nerbonne JM, Levitan ES (1997) Distribution, splicing and glucocorticoid-induced expression of cardiac alpha 1C and alpha 1D voltage-gated Ca2+ channel mRNAs. J Mol Cell Cardiol 29:3035–3042. doi:10.1006/jmcc.1997.0532

    Article  CAS  PubMed  Google Scholar 

  99. Dolmetsch RE, Pajvani U, Fife K, et al. (2001) Signaling to the nucleus by an L-type calcium channel-calmodulin complex through the MAP kinase pathway. Science 294:333–339. doi:10.1126/science.1063395

    Article  CAS  PubMed  Google Scholar 

  100. Weick JP, Groth RD, Isaksen AL, Mermelstein PG (2003) Interactions with PDZ proteins are required for L-type calcium channels to activate cAMP response element-binding protein-dependent gene expression. J Neurosci 23:3446–3456

    CAS  PubMed  Google Scholar 

  101. Moosmang S, Haider N, Klugbauer N, et al. (2005) Role of hippocampal Cav1.2 Ca2+ channels in NMDA receptor-independent synaptic plasticity and spatial memory. J Neurosci 25:9883–9892. doi:10.1523/JNEUROSCI.1531-05.2005

    Article  CAS  PubMed  Google Scholar 

  102. Splawski I, Timothy KW, Sharpe LM, et al. (2004) Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 119:19–31. doi:10.1016/j.cell.2004.09.011

    Article  CAS  PubMed  Google Scholar 

  103. Olson PA, Tkatch T, Hernandez-Lopez S, et al. (2005) G-protein-coupled receptor modulation of striatal CaV1.3 L-type Ca2+ channels is dependent on a shank-binding domain. J Neurosci 25:1050–1062. doi:10.1523/JNEUROSCI.3327-04.2005

    Article  CAS  PubMed  Google Scholar 

  104. Chan CS, Guzman JN, Ilijic E, et al. (2007) “rejuvenation” protects neurons in mouse models of Parkinson’s disease. Nature 447:1081–1086. doi:10.1038/nature05865

    Article  CAS  PubMed  Google Scholar 

  105. Simpson ER (2003) Sources of estrogen and their importance. J Steroid Biochem Mol Biol 86:225–230

    Article  CAS  PubMed  Google Scholar 

  106. Wittliff JL, Andres SA (2014) Estrogens I. In: Encycl. Toxicol. Elsevier, pp 462–466

  107. Carreau S (2003) Estrogens--male hormones? Folia Histochem Cytobiol 41:107–111

    CAS  PubMed  Google Scholar 

  108. Liang J, Shang Y (2013) Estrogen and cancer. Annu Rev Physiol 75:225–240. doi:10.1146/annurev-physiol-030212-183708

    Article  CAS  PubMed  Google Scholar 

  109. Bolt HM (1979) Metabolism of estrogens—natural and synthetic. Pharmacol Ther 4:155–181. doi:10.1016/0163-7258(79)90018-4

    Article  CAS  PubMed  Google Scholar 

  110. Holinka CF, Diczfalusy E, Coelingh Bennink HJT (2008) Estetrol: a unique steroid in human pregnancy. J Steroid Biochem Mol Biol 110:138–143. doi:10.1016/j.jsbmb.2008.03.027

    Article  CAS  PubMed  Google Scholar 

  111. Thomas MP, Potter BVL (2013) The structural biology of oestrogen metabolism. J Steroid Biochem Mol Biol 137:27–49. doi:10.1016/j.jsbmb.2012.12.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Boon WC, Chow JDY, Simpson ER (2010) The multiple roles of estrogens and the enzyme aromatase. Prog Brain Res 181:209–232. doi:10.1016/S0079-6123(08)81012-6

    Article  CAS  PubMed  Google Scholar 

  113. Russell JF, Wong JC, Grumbach MM (2014) Aromatase deficiency and aromatase excess. In: Genet. Steroid Disord. Elsevier, pp 165–190

  114. Maia H Jr, Haddad C (2012) Correlation between aromatase expression in the eutopic endometrium of symptomatic patients and the presence of endometriosis. Int J Womens Health 61. doi:10.2147/IJWH.S29154

  115. Bulun SE, Lin Z, Zhao H, et al. (2009) Regulation of aromatase expression in breast cancer tissue. Ann N Y Acad Sci 1155:121–131. doi:10.1111/j.1749-6632.2009.03705.x

    Article  CAS  PubMed  Google Scholar 

  116. Boutros C, Gary M, Baldwin K, Somasundar P (2012) Gallbladder cancer: past, present and an uncertain future. Surg Oncol 21:e183–e191. doi:10.1016/j.suronc.2012.08.002

    Article  CAS  PubMed  Google Scholar 

  117. Crider A, Thakkar R, Ahmed AO, Pillai A (2014) Dysregulation of estrogen receptor beta (ERβ), aromatase (CYP19A1), and ER co-activators in the middle frontal gyrus of autism spectrum disorder subjects. Mol Autism 5:46. doi:10.1186/2040-2392-5-46

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Weiser MJ, Foradori CD, Handa RJ (2008) Estrogen receptor beta in the brain: from form to function. Brain Res Rev 57:309–320. doi:10.1016/j.brainresrev.2007.05.013

    Article  CAS  PubMed  Google Scholar 

  119. Smejkalova T, Woolley CS (2010) Estradiol acutely potentiates hippocampal excitatory synaptic transmission through a presynaptic mechanism. J Neurosci 30:16137–16148. doi:10.1523/JNEUROSCI.4161-10.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Yankova M, Hart SA, Woolley CS (2001) Estrogen increases synaptic connectivity between single presynaptic inputs and multiple postsynaptic CA1 pyramidal cells: a serial electron-microscopic study. Proc Natl Acad Sci 98:3525–3530. doi:10.1073/pnas.051624598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. MacLusky NJ, Luine VN, Hajszan T, Leranth C (2005) The 17alpha and 17beta isomers of estradiol both induce rapid spine synapse formation in the CA1 hippocampal subfield of ovariectomized female rats. Endocrinology 146:287–293. doi:10.1210/en.2004-0730

    Article  CAS  PubMed  Google Scholar 

  122. Zadran S, Qin Q, Bi X, et al. (2009) 17-Beta-estradiol increases neuronal excitability through MAP kinase-induced calpain activation. Proc Natl Acad Sci U S A 106:21936–21941. doi:10.1073/pnas.0912558106

    Article  PubMed  PubMed Central  Google Scholar 

  123. Fatehi M, Fatehi-Hassanabad Z (2008) Effects of 17β-estradiol on neuronal cell excitability and neurotransmission in the suprachiasmatic nucleus of rat. Neuropsychopharmacology 33:1354–1364. doi:10.1038/sj.npp.1301523

    Article  CAS  PubMed  Google Scholar 

  124. Foy MR, Baudry M, Akopian GK, Thompson RF (2010) Regulation of hippocampal synaptic plasticity by estrogen and progesterone. Vitam Horm 82:219–239. doi:10.1016/S0083-6729(10)82012-6

    Article  CAS  PubMed  Google Scholar 

  125. Ogiue-Ikeda M, Tanabe N, Mukai H, et al. (2008) Rapid modulation of synaptic plasticity by estrogens as well as endocrine disrupters in hippocampal neurons. Brain Res Rev 57:363–375. doi:10.1016/j.brainresrev.2007.06.010

    Article  CAS  PubMed  Google Scholar 

  126. Foy M, Baudry M, Thompson R (2005) Estrogen and hippocampal synaptic plasticity. Neuron Glia Biol 1:327. doi:10.1017/S1740925X05000165

    Article  Google Scholar 

  127. Fu X, Simoncini T (2008) Extra-nuclear signaling of estrogen receptors. IUBMB Life 60:502–510. doi:10.1002/iub.80

    Article  CAS  PubMed  Google Scholar 

  128. Marino M, Galluzzo P, Ascenzi P (2006) Estrogen signaling multiple pathways to impact gene transcription. Curr Genomics 7:497–508. doi:10.2174/138920206779315737

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Segars JH, Driggers PH (2002) Estrogen action and cytoplasmic signaling cascades. Part I: membrane-associated signaling complexes. Trends Endocrinol Metab 13:349–354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Zhao L, Chen S, Ming Wang J, Brinton RD (2005) 17beta-estradiol induces Ca2+ influx, dendritic and nuclear Ca2+ rise and subsequent cyclic AMP response element-binding protein activation in hippocampal neurons: a potential initiation mechanism for estrogen neurotrophism. Neuroscience 132:299–311. doi:10.1016/j.neuroscience.2004.11.054

    Article  CAS  PubMed  Google Scholar 

  131. Beyer C, Raab H (1998) Nongenomic effects of oestrogen: embryonic mouse midbrain neurones respond with a rapid release of calcium from intracellular stores. Eur J Neurosci 10:255–262

    Article  CAS  PubMed  Google Scholar 

  132. Chaban VV, Lakhter AJ, Micevych P (2004) A membrane estrogen receptor mediates intracellular calcium release in astrocytes. Endocrinology 145:3788–3795. doi:10.1210/en.2004-0149

    Article  CAS  PubMed  Google Scholar 

  133. Kuo J, Hamid N, Bondar G, et al. (2010) Membrane estrogen receptors stimulate intracellular calcium release and progesterone synthesis in hypothalamic astrocytes. J Neurosci 30:12950–12957. doi:10.1523/JNEUROSCI.1158-10.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Brewer LD, Dowling ALS, Curran-Rauhut MA, et al. (2009) Estradiol reverses a calcium-related biomarker of brain aging in female rats. J Neurosci 29:6058–6067. doi:10.1523/JNEUROSCI.5253-08.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Sribnick EA, Del Re AM, Ray SK, et al. (2009) Estrogen attenuates glutamate-induced cell death by inhibiting Ca2+ influx through L-type voltage-gated Ca2+ channels. Brain Res 1276:159–170. doi:10.1016/j.brainres.2009.04.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Sánchez JC, López-Zapata DF, Pinzón OA (2014) Effects of 17beta-estradiol and IGF-1 on L-type voltage-activated and stretch-activated calcium currents in cultured rat cortical neurons. Neuro Endocrinol Lett 35:724–732

    PubMed  Google Scholar 

  137. Xu C, Roepke TA, Zhang C, et al. (2008) Gonadotropin-releasing hormone (GnRH) activates the M-current in GnRH neurons: an Autoregulatory negative feedback mechanism? Endocrinology 149:2459–2466. doi:10.1210/en.2007-1178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Acaz-Fonseca E, Ávila-Rodriguez, Garcia-Segura LM, Barreto GE (2016) Regulation of astroglia by gonadal steroid hormones under physiological and pathological conditions. Prog Neurobiol. doi:10.1016/j.pneurobio.2016.06.002

    PubMed  Google Scholar 

  139. Lanussa OH, Ávila-Rodriguez M, García-Segura LM, González J, Echeverria V, Aliev G, Barreto GE (2016) Microglial dependent protective effects of neuroactive steroids. CNS Neurol Disord Drug Targets 15(2):242–249. doi:10.2174/1871527315666160202122032

    Article  CAS  PubMed  Google Scholar 

  140. Avila-Rodriguez M, Garcia-Segura LM, Hidalgo-Lanussa O, Baez E, Gonzalez J, Barreto GE (2016) Tibolone protects astrocytic cells from glucose deprivation through a mechanism involving estrogen receptor beta and the upregulation of neuroglobin expression. Mol Cell Endocrinol 433:35–46. doi:10.1016/j.mce.2016.05.024

    Article  CAS  PubMed  Google Scholar 

  141. Toro-Urrego N, Garcia-Segura LM, Echeverria V, Barreto GE (2016) Testosterone protects mitochondrial function and regulates neuroglobin expression in astrocytic cells exposed to glucose deprivation. Front Aging Neurosci 8:152. doi:10.3389/fnagi.2016.00152

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was in part funded by PUJ grants #5544 and 5608 to GEB, and #6243, 5619 and 6371 to JG.

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Authors and Affiliations

  1. Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá D.C., Colombia

    Nelson E. Vega-Vela, Daniel Osorio, Marco Avila-Rodriguez, Janneth Gonzalez & George E. Barreto

  2. Instituto Cajal, CSIC, Madrid, Spain

    Luis Miguel García-Segura

  3. Universidad San Sebastián, Lientur 1457, 4030000, Concepción, Chile

    Valentina Echeverria

  4. Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Santiago, Chile

    George E. Barreto

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  1. Nelson E. Vega-Vela
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  2. Daniel Osorio
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  3. Marco Avila-Rodriguez
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  4. Janneth Gonzalez
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  5. Luis Miguel García-Segura
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  7. George E. Barreto
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Correspondence to George E. Barreto.

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Nelson E. Vega-Vela and Daniel Osorio contributed equally to this work.

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Vega-Vela, N.E., Osorio, D., Avila-Rodriguez, M. et al. L-Type Calcium Channels Modulation by Estradiol. Mol Neurobiol 54, 4996–5007 (2017). https://doi.org/10.1007/s12035-016-0045-6

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