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Pharmacological Evidence for the Involvement of Calcium Entry through TRPV1 Channels in Nifedipine-Induced [Ca2+]i Elevation in Gingival Fibroblasts

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DOI: 10.4236/pp.2012.34057    4,355 Downloads   6,968 Views  


Background: Among anti-hypertension drugs, calcium (Ca2+) antagonists cause gingival overgrowth as a side effect. We previously discovered that this side effect was due to elevation of the calcium concentration in the cytosol ([Ca2+]i). Ca2+ entry through non-selective cation channels (NSCCs) and Ca2+ release from intracellular Ca2+ stores are involved in this [Ca2+]i elevation. Furthermore, we discovered that calcium-sensing receptors (CaSRs) participate in nifedipine-induced [Ca2+]i elevation. Transient receptor potential (TRP) channels have been identified as NSCCs. In the present study, we undertook experiments to determine if TRPV1 channels are present in gingival fibroblasts and to ascertain if nifedipine-activated NSCCs are TRPV1 channels. Methods Normal human gingival fibroblast Gin-1 cells were used. The [Ca2+]i was measured using a video-imaging analysis system with the Ca2+-sensitive fluorescent dye fura-2/AM. Results: The NSCC inhibitor SKF96365 significantly inhibited nifedipine-induced [Ca2+]i elevation. TRPV1 channel agonists such as capsaicin, olvanil and resiniferatoxin concentration-dependently elevated the [Ca2+]i. The TRPV1 channel activator anandamide concentration-dependently increased the [Ca2+]i. The TRPV1 channel antagonists capsazepine, AMG9810, iodoresiniferatoxin, ruthenium red, and SB366791 significantly inhibited nifedipine-induced [Ca2+]i elevation. Conclusion: These results suggest that Ca2+ entry through TRPV1 channels is involved in the nifedipine-induced [Ca2+]i elevation seen in gingival fibroblasts. We describe here a modified version of our ‘calcium trigger theory’.

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The authors declare no conflicts of interest.

Cite this paper

T. Hattori, T. Ara and Y. Fujinami, "Pharmacological Evidence for the Involvement of Calcium Entry through TRPV1 Channels in Nifedipine-Induced [Ca2+]i Elevation in Gingival Fibroblasts," Pharmacology & Pharmacy, Vol. 3 No. 4, 2012, pp. 427-432. doi: 10.4236/pp.2012.34057.


[1] M. Kataoka, J. Kido, Y. Shinohara and T. Nagata, “Drug-induced gingival overgrowth-a review,” Biological and Pharmaceutical Bulletin, Vol. 28, No. 10, 2005, pp. 1817-1821.
[2] T. Hattori and PL.Wang, “Elevation of cytosolic calcium level triggers calcium antagonist-induced gingival overgrowth,” European Journal of Pharmacology, Vol. 583, No. 2, 2008, pp. 37-39.
[3] T. Hattori and PL.Wang, “Calcium antagonist isradipine-induced calcium influx through nonselective cation channels in human gingival fibroblasts,” European Journal of Medical Research, Vol. 11, No. 3, 2006, pp. 93-96.
[4] T. Hattori and PL. Wang, “Participation of tyrosine kinase and phosphosliapse Cγ in isradipine-induced proliferation of cultured human gingival fibroblasts,” European Journal of Medical Research, Vol. 10, No. 12, 2005, pp. 543-546.
[5] T. Hattori, T. Ara and Y. Fujinami, “Pharmacological evidences for stimulation of calcium-sensing receptors by nifedipine in gingival fibroblasts,” Journal of Pharmacology and Pharmacotherapeutics, Vol. 2, No. 1, 2011, pp. 30-35.
[6] DS. McGehee, M. Aldersberg, KP. Liu, MJS. SC. Hsuing, MJS. Heath and H. Tamir, “Mechanism of extracllular Ca2+ receptor-stimulated hormone release from sheep thyroid parafollicular cells,” Journal of Physiology, Vol. 502, No. 1, 1997, pp. 31-44.
[7] C. Remy, P. Kirchihoff, P. Hafner, SM. Busque, MK. Müller, JP. Geibel and AW. Carsten, “Stimulatory pathways of the calcium-sensing receptor on acid secretion in freshly isolated human gastric glands,” Cellular Physiology and Biochemistry, Vol. 19, No. 11, 2007, 33-42.
[8] M. Bandell, GM. Story, SW. Hwang, V. Viswanath, SR. Eid, MJ. Petrus, TJ. Early and A. Patapoutian, “Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin,” Neuron, Vol. 41, No. 6, 2004, pp. 849-857.
[9] A. Fleig and R. Penner, “The TRPM ion channel subfamily: molecular, biophysical and functional features,” Trends in Pharmacological Sciences, Vol. 25, No. 12, 2004, pp. 633-639.
[10] M. Freichel, R. Vennekens, J. Olausson, M. Hoffmann, C. Müller, S. Stolz, J. Scheunemann, P. Weissgerber and V. Flockerzi, “Functional role of TRPC proteins in vivo: lessons from TRPC-deficient mouse models,” Biochemical and Biophysical Research Communications, Vol. 32, No. 4, 2004, pp. 1352-1358.
[11] R. Inoue, T. Okada, H. Onoue, Y Hara, S. Shimizu, S. Naitoh, Y. Ito and Y. Mori, “The transient receptor potential protein homologue TRP6 is the essential component of vascular α1-adrenoceptor-ativated Ca2+-permeable cation channel,” Circulation Research, Vol. 88, No. 3, 2001, pp. 325-332.
[12] GP. Ahern, IM. Brooks, L. Miyares and XB.Wang, “Extracellular cations sensitize and gate capsaicin receptor TRPV1 modulating pain signaling,” Journal of Neuroscience, Vol. 25, No. 21, 2005, pp. 5109-5116.
[13] NR. Gavva, R. Tamir, Y. Qu, L. Kliosky, TJ. Zhang, D. Immke, J. Wang, D. Zhu, TW. Vanderah, F. Porreca, EM. Doherty, MH. Norman, KD. Wild, AW. Bannon, JC. Louis and JJ. Treanor, “AMG 9810 [(E)-3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4] dio-xin-6-yl)acrylamide], a novel vanilloid receptor 1 (TRPV1) antagonists with antihyperalgestic properties,” Journal of Pharmacology and Experimental Therapeutics, Vol. 313, No. 1, 2005, pp. 474-484.
[14] YV. Medvedeva, MS. Kim and YM. Usachev, “Mechanism of prolonged presynaptic Ca2+ signaling and glutamate release induced by TRPV1 activation in rat sensory neurons,” Journal of Neuroscience, Vol. 28, No. 20, 2008, pp. 5295-5311.
[15] SE. Mydral and Steyger DS, “TRPV1 regulators mediate gentamicin penetration of cultured kidney cells,“ Hearing Research, Vol. 204, No. 1-2, 2005, pp. 170-182.
[16] T. Takada and Y. Mori, “Transient receptor potential channels,” Folia Pharmacologica Japonica, Vol. 139, No. 1, 2012, pp. 39-40.
[17] M. Stelt and V. Marzo, “Endovanilloids putative endogeneous ligands of transient receptor potential vanilloid 1 channels,” European Journal of Biochemistry,” Vol. 271, No. 10, 2004, pp. 1827-1834.
[18] YE. Hiani, A. Ahidouch, M. Roudbaraki, S. Guenin, G. Brolé and H. Ouadid-Ahidouch, “Calcium-sensing receptor stimulation induces nonselective cation channels activation in breast cancer cells,” Journal of Membrane Biology, Vol. 211, No. 2, 2006, pp. 127-137.
[19] O. Rey, SH. Young, R. Papazyan, M. Shapiro and E. Rozengurt, “Requirement of the TRPC1 cation channel in the generation of transient Ca2+ oscillations by the calcium-sensing receptor,” Journal of Biological Chemistry, Vol. 281, No. 50, 2006, pp. 38730-38737.
[20] YC. Chen, HH. Willcockson and JG. Valtschanoff, “Influence of the vanilloid receptor TRPV1 on the activation of spinal cord glia in mouse models of pain,” Experimental Neurology, Vol. 220, No. 2, 2009, pp. 383-390.
[21] AE. Chávez, CQ. Chiu and PE. Castillo, “TRPV1 activation by endogeneous anandamide triggers post-synaptic LTD in dentate gyrus,” Nature Neuroscience, Vol. 13, No. 12, 2010, pp. 1511-1518.
[22] M. Nishida, K. Sugimoto, Y. Hara, E. Mori, T. Morii and T. Kurosaki, “Amplification of receptor signaling by Ca2+ entry-mediated translocation and activation of PLCγ2 in B lymphocytes,” The EMBO Journal, Vol. 22, No. 18, 2003, 4677-4688.

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