Calcium Pumps and Keratinocytes: Lessons From Darier's Disease and Hailey-Hailey Disease

J. Dhitavat; R.J. Fairclough; A. Hovnanian; S.M. Burge


The British Journal of Dermatology. 2004;150(5) 

In This Article

Distribution of SERCA and SPCA

Three genes, ATP2A1, ATP2A2 and ATP2A3, encode three types of SERCA protein, SERCA1, SERCA2 and SERCA3, and alternative splicing of the primary transcripts gives rise to at least nine SERCA isoforms with different functions.[33,34,35,36,37]

SERCA1a is expressed predominantly in adult fast-twitch muscle and SERCA1b is the alternatively spliced neonatal form of SERCA1. The SERCA2a isoform is found mainly in adult slow-twitch cardiac and skeletal muscle, as well as neonatal muscle.[37,38] SERCA2a is expressed at a much lower level in nonmuscle cells including keratinocytes.[16] In contrast, the SERCA2b isoform is the principal form of the Ca2+-ATPase in smooth muscles and nonmuscle tissues, including keratinocytes, where it is considered to play an essential housekeeping role.[16] Expression of SERCA2 seems stronger in basal epidermal keratinocytes than in suprabasal cells.[39]

SERCA3 is highly expressed in intestine, lung and spleen as well as a variety of nonmuscle cells of endothelial, epithelial and haematopoietic origin, but SERCA3 is not detected in epidermis or hair follicles, although it is present in sweat ducts.34,37,[38]

Two genes (ATP2C1 and ATP2C2) encode human SPCA proteins 1 and 2, and alternative splicing at the C-terminus generates additional diversity.[13,14,40,41]ATP2C1 mRNA is present in all tissues that have been examined, suggesting that the human SPCA1 protein performs a vital housekeeping function.[42,43]ATP2C2 mRNA has been found along much of the gastrointestinal tract.[41,43]

Why do mutations in genes encoding these ATPases, apparently essential in so many cell types, cause diseases that are limited to the skin? Although neuropsychiatric conditions such as bipolar disorder have been linked to Darier's disease, such associations are infrequent and other genes seem to be responsible for neuropsychiatric manifestations in these patients.[44,45] Most physiological systems compensate for the abnormality in Darier's disease. Studies in SERCA2± mice have revealed considerable plasticity and adaptability of Ca2+ signalling and Ca2+-dependent cellular functions in vivo,[46] but human keratinocytes are not able to compensate for loss of SERCA2 function, perhaps because, unlike most other tissues, keratinocytes lack SERCA3.[38]

While both the SERCA and the SPCA pumps are involved in Ca2+ uptake into the Golgi apparatus, human keratinocytes rely mainly on SPCA1 pumps for loading the Golgi stores with Ca2+.[47,48] This may explain, at least partially, why mutations in Hailey-Hailey disease preferentially affect the skin.