Abnormal intracellular Ca2+ homeostasis and disease

A whole range of cell functions are regulated by the free cytosolic Ca2+ co ncentration. Activator Ca2+ from the extracellular space enters the cell th rough various types of Ca2+ channels and sometimes the Na+/Ca2+-exchanger, and is actively extruded from the cell by Ca2+ pumps and Na+/Ca2+-exchanger s. Activator Ca2+ can also be released from internal Ca2+ stores through in ositol trisphosphate or ryanodine receptors and is taken up into these orga nelles by means of Ca2+ pumps. The resulting Ca2+ signal is highly organize d in space, frequency and amplitude because the localization and the integr ated free cytosolic Ca2+ concentration over time contain specific informati on. Mutations or functional abnormalities in the various Ca2+ transporters, which in vitro seem to induce trivial functional alterations, therefore, o ften lead to a plethora of diseases. Skeletal-muscle pathology can be cause d by mutations in ryanodine receptors (malignant hyperthermia, porcine stre ss syndrome, central-core disease), dihydropyridine receptors (familial hyp okalemic periodic paralysis, malignant hyperthermia, muscular dysgenesis) o r Ca2+ pumps (Brody disease). Ca2+-pump mutations in cutaneous epidermal ke ratinocytes and cochlear hair cells lead to, skin diseases (Darier and Hail ey-Hailey) and hearing/vestibular problems respectively. Mutated Ca2+ chann els in the photoreceptor plasma membrane cause vision problems. Hemiplegic migraine, spinocerebellar ataxia type-6, one form of episodic ataxia and so me forms of epilepsy can be due to mutations in plasma-membrane Ca2+ channe ls, while antibodies against these channels play a pathogenic role in all p atients with the Lambert-Eaton myasthenic syndrome and may be of significan ce in sporadic amyotrophic lateral sclerosis. Brain inositol trisphosphate receptors have been hypothesized to contribute to the pathology in opisthot onos mice, manic-depressive illness and perhaps Alzheimer's disease. Variou s abnormalities in Ca2+-handling proteins have been described in heart duri ng aging, hypertrophy, heart failure and during treatment with immunosuppre ssive drugs and in diabetes mellitus. In some instances, disease-causing mu tations or abnormalities provide us with new insights into the cell biology of the various Ca2+ transporters. (C) 2000 Harcourt Publishers Ltd.