title: Effects of 2,3-butanedione 2-monoxime on Ca2+ release channels (ryanodine receptors) of cardiac and skeletal muscle.
abstract: Single channel and [3H]ryanodine binding measurements were performed to test for a direct functional interaction between 2,3-butanedione 2-monoxime (BDM) and the skeletal and cardiac muscle sarcoplasmic reticulum Ca2+ release channels (ryanodine receptors). Single channel measurements were carried out in symmetric 0.25 m KCl media using the planar lipid bilayer method. BDM (1-10 mm) activated suboptimally Ca2+-activated (0.5-1 microM free Ca2+) single, purified and native cardiac and skeletal release channels in a concentration-dependent manner by increasing the number of channel events without a change of single channel conductances. BDM activated the two channel isoforms when added to either side of the bilayer. At a maximally activating cytosolic Ca2+ concentration of 20 microM, BDM was without effect on the cardiac channel, whereas it inhibited skeletal channel activities with IC50 approximately 2.5 mm. In agreement with single channel measurements, high-affinity [3H]ryanodine binding to the two channel isoforms was increased in a concentration-dependent manner at </=1 microM Ca2+. BDM was without a noticeable effect at low (</=0.01 microM) Ca2+ concentrations. At 20 microM Ca2+, BDM inhibited the skeletal but not cardiac channel. These results suggest that BDM regulates the Ca2+ release channels from the sarcoplasmic reticulum of skeletal and cardiac muscle in a concentration, Ca2+ and tissue-dependent manner.
authors.affiliation: Departments of Biochemistry and Biophysics, and Physiology, University of North Carolina, Chapel Hill, NC 27599-7260, USA.
authors.forename: A
authors.initials: A
authors.lastname: Tripathy
authors.forename: L
authors.initials: L
authors.lastname: Xu
authors.forename: D A
authors.initials: DA
authors.lastname: Pasek
authors.forename: G
authors.initials: G
authors.lastname: Meissner
mesh_terms: D000818:Animals; D002118:Calcium / Q000502:physiology; D002801:Cholinesterase Reactivators / Q000494:pharmacology*; D003931:Diacetyl / Q000031:analogs & derivatives* / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000502:physiology*; D015640:Ion Channel Gating / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D018482:Muscle, Skeletal / Q000502:physiology*; D009200:Myocardial Contraction / Q000187:drug effects; D018408:Patch-Clamp Techniques; D011817:Rabbits; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000502:physiology*
chemical_list: D002801:Cholinesterase Reactivators; D019837:Ryanodine Receptor Calcium Release Channel; C004717:diacetylmonoxime; D003931:Diacetyl; D002118:Calcium