INTRODUCTION Ca 2+ is a very important signaling molecule within cells [1]. Many cellular functions are directly or indirectly reg- ulated by the free cytosolic Ca 2+ concentration ([Ca 2+ ] i ). The [Ca 2+ ] i must be very tightly regulated in time, in space and in amplitude because cells manage to extract specific information from these three parameters. Because Ca 2+ is such an important signaling molecule, mutations causing drastic functional changes in intracel- lular Ca 2+ homeostasis are most likely not compatible with life [2]. Mutations or abnormalities in one of the var- ious proteins involved in intracellular Ca 2+ regulation, which in vitro seem only to induce trivial alterations in the function of the protein, often lead to a plethora of diseases (Table 1). The molecular biology and functional regulation of many of the proteins involved in controlling the [Ca 2+ ] i are now quite well understood. Scientists are now begin- ning to characterize altered biophysical properties of mutant proteins in isolation. The next challenge will be to understand how dysfunction of a single ion channel or pump may result in a diverse array of diseases. Review Abnormal intracellular Ca 2+ homeostasis and disease L. Missiaen, 1 W. Robberecht, 2 L. Van Den Bosch, 2 G. Callewaert, 1 J. B. Parys, 1 F. Wuytack, 1 L. Raeymaekers, 1 B. Nilius, 1 J. Eggermont, 1 H. De Smedt 1 1 Laboratory of Physiology, K.U.Leuven Campus Gasthuisberg O/N, Leuven, Belgium 2 Laboratory of Neurobiology, K.U.Leuven Campus Gasthuisberg O/N, Leuven, Belgium Summary A whole range of cell functions are regulated by the free cytosolic Ca 2+ concentration. Activator Ca 2+ from the extracellular space enters the cell through various types of Ca 2+ channels and sometimes the Na + /Ca 2+ -exchanger, and is actively extruded from the cell by Ca 2+ pumps and Na + /Ca 2+ -exchangers. Activator Ca 2+ can also be released from internal Ca 2+ stores through inositol trisphosphate or ryanodine receptors and is taken up into these organelles by means of Ca 2+ pumps. The resulting Ca 2+ signal is highly organized in space, frequency and amplitude because the localization and the integrated free cytosolic Ca 2+ concentration over time contain specific information. Mutations or functional abnormalities in the various Ca 2+ transporters, which in vitro seem to induce trivial functional alterations, therefore, often lead to a plethora of diseases. Skeletal-muscle pathology can be caused by mutations in ryanodine receptors (malignant hyperthermia, porcine stress syndrome, central-core disease), dihydropyridine receptors (familial hypokalemic periodic paralysis, malignant hyperthermia, muscular dysgenesis) or Ca 2+ pumps (Brody disease). Ca 2+ - pump mutations in cutaneous epidermal keratinocytes and cochlear hair cells lead to, skin diseases (Darier and Hailey- Hailey) and hearing/vestibular problems respectively. Mutated Ca 2+ channels in the photoreceptor plasma membrane cause vision problems. Hemiplegic migraine, spinocerebellar ataxia type-6, one form of episodic ataxia and some forms of epilepsy can be due to mutations in plasma-membrane Ca 2+ channels, while antibodies against these chan- nels play a pathogenic role in all patients with the Lambert-Eaton myasthenic syndrome and may be of significance in sporadic amyotrophic lateral sclerosis. Brain inositol trisphosphate receptors have been hypothesized to contribute to the pathology in opisthotonos mice, manic-depressive illness and perhaps Alzheimer’s disease. Various abnormalities in Ca 2+ -handling proteins have been described in heart during aging, hypertrophy, heart failure and during treatment with immunosuppressive drugs and in diabetes mellitus. In some instances, disease-causing mutations or abnormali- ties provide us with new insights into the cell biology of the various Ca 2+ transporters. © 2000 Harcourt Publishers Ltd 1 Correspondence to: Dr Ludwig Missiaen. Laboratorium voor Fysiologie, K.U.Leuven Campus Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. Tel.: +32 16 345720; Fax: +32 16 345991; E-mail: Ludwig.Missiaen@med.kuleuven.ac.be Cell Calcium (2000) 28 (1), 1–21 © 2000 Harcourt Publishers Ltd doi: 10.1054/ceca.2000.0131, available online at http://www.idealibrary.com on