title: Abnormal intracellular ca(2+)homeostasis and disease.
abstract: 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 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 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 abnormalities provide us with new insights into the cell biology of the various Ca(2+)transporters.
authors.affiliation: Laboratory of Physiology, K.U.Leuven Campus Gasthuisberg O/N, Leuven, Belgium. Ludwig.Missiaen@med.kuleven.ac.be
authors.forename: L
authors.initials: L
authors.lastname: Missiaen
authors.forename: W
authors.initials: W
authors.lastname: Robberecht
authors.forename: L
authors.initials: L
authors.lastname: van den Bosch
authors.forename: G
authors.initials: G
authors.lastname: Callewaert
authors.forename: J B
authors.initials: JB
authors.lastname: Parys
authors.forename: F
authors.initials: F
authors.lastname: Wuytack
authors.forename: L
authors.initials: L
authors.lastname: Raeymaekers
authors.forename: B
authors.initials: B
authors.lastname: Nilius
authors.forename: J
authors.initials: J
authors.lastname: Eggermont
authors.forename: H
authors.initials: H
authors.lastname: De Smedt
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics; D020746:Calcium Channels, L-Type / Q000235:genetics; D002128:Calcium Metabolism Disorders / Q000378:metabolism*; D020013:Calcium Signaling; D002135:Calcium-Binding Proteins / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000235:genetics; D006706:Homeostasis; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors; D051379:Mice; D008954:Models, Biological; D009119:Muscle Contraction; D009154:Mutation; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D050052:TRPC Cation Channels
chemical_list: D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D002135:Calcium-Binding Proteins; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D019837:Ryanodine Receptor Calcium Release Channel; D050052:TRPC Cation Channels; C096351:transient receptor potential cation channel, subfamily C, member 1; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D002118:Calcium