Abnormal intracellular Ca2+ homeostasis and disease

A whole range of cell functions are regulated by the free cytosolic Ca2+ concentration. Activator Ca2+ from the extracellular space enters the cell through various types of Ca2+ channels and sometimes the Na+/Ca2+-exchanger, and is actively extruded from the cell by Ca2+ pumps and Na+/Ca2+-exchangers. Activator Ca2+ can also be released from internal Ca2+ stores through inositol trisphosphate or ryanodine receptors and is taken up into these organelles by means of Ca2+ pumps. The resulting Ca2+ signal is highly organized in space, frequency and amplitude because the localization and the integrated free cytosolic Ca2+ concentration over time contain specific information. Mutations or functional abnormalities in the various Ca2+ 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 Ca2+ pumps (Brody disease). Ca2+-pump mutations in cutaneous epidermal keratinocytes and cochlear hair cells lead to, skin diseases (Darier and Hailey-Hailey) and hearing/vestibular problems respectively. Mutated Ca2+ 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 Ca2+ channels, while antibodies against these channels 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 Ca2+-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 abnormalities provide us with new insights into the cell biology of the various Ca2+ transporters. (C) 2000 Harcourt Publishers Ltd.