title: Up-regulation of transient receptor potential canonical 1 (TRPC1) following sarco(endo)plasmic reticulum Ca2+ ATPase 2 gene silencing promotes cell survival: a potential role for TRPC1 in Darier's disease.
abstract: The mechanism(s) involved in regulation of store operated calcium entry in Darier's disease (DD) is not known. We investigated the distribution and function of transient receptor potential canonical (TRPC) in epidermal skin cells. DD patients demonstrated up-regulation of TRPC1, but not TRPC3, in the squamous layers. Ca2+ influx was significantly higher in keratinocytes obtained from DD patients and showed enhanced proliferation compared with normal keratinocytes. Similar up-regulation of TRPC1 was also detected in epidermal layers of SERCA2+/- mice. HaCaT cells expressed TRPC1 in the plasma membrane. Expression of sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA)2 small interfering RNA (siRNA) in HaCaT cells increased TRPC1 levels and thapsigargin-stimulated Ca2+ influx, which was blocked by store-operated calcium entry inhibitors. Thapsigargin-stimulated intracellular Ca2+ release was decreased in DD cells. DD keratinocytes exhibited increased cell survival upon thapsigargin treatment. Alternatively, overexpression of TRPC1 or SERCA2-siRNA in HaCaT cells demonstrated resistance to thapsigargin-induced apoptosis. These effects were dependent on external Ca2+ and activation of nuclear factor-kappaB. Isotretinoin reduced Ca2+ entry in HaCaT cells and decreased survival of HaCaT and DD keratinocytes. These findings put forward a novel consequence of compromised SERCA2 function in DD wherein up-regulation of TRPC1 augments cell proliferation and restrict apoptosis. We suggest that the anti-apoptotic effect of TRPC1 could potentially contribute to abnormal keratosis in DD.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA.
authors.forename: Biswaranjan
authors.initials: B
authors.lastname: Pani
authors.forename: Eric
authors.initials: E
authors.lastname: Cornatzer
authors.forename: William
authors.initials: W
authors.lastname: Cornatzer
authors.forename: Dong-Min
authors.initials: DM
authors.lastname: Shin
authors.forename: Mark R
authors.initials: MR
authors.lastname: Pittelkow
authors.forename: Alain
authors.initials: A
authors.lastname: Hovnanian
authors.forename: Indu S
authors.initials: IS
authors.lastname: Ambudkar
authors.forename: Brij B
authors.initials: BB
authors.lastname: Singh
mesh_terms: D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D007644:Darier Disease / Q000378:metabolism*; D020868:Gene Silencing; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics*; D012867:Skin / Q000166:cytology / Q000378:metabolism; D050052:TRPC Cation Channels / Q000378:metabolism*; D019284:Thapsigargin / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D016328:NF-kappa B; D050052:TRPC Cation Channels; C096351:transient receptor potential cation channel, subfamily C, member 1; D019284:Thapsigargin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium