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K+ K+ Ca+ Tropomyosin alpha-1 chain Tropomyosin beta chain Beta-1 adrenergic receptor cAMP-dependent protein kinase type I-alpha regulatory subunit Voltage- dependent L-type calcium channel subunit alpha-1C Voltage- dependent calcium channel subunit alpha-2/delta-2 Voltage- dependent L-type calcium channel subunit beta-1 Ryanodine receptor 2 Muscarinic acetylcholine receptor M2 Cardiac phospholamban Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 Inward rectifier potassium channel 4 Potassium voltage-gated channel subfamily D member 3 Kv channel- interacting protein 2 Potassium voltage-gated channel subfamily A member 5 Disks large homolog 1 Potassium voltage-gated channel subfamily KQT member 1 Potassium voltage-gated channel subfamily E member 1 Potassium voltage-gated channel subfamily E member 2 ATP-binding cassette sub-family C member 8 ATP-sensitive inward rectifier potassium channel 8 ATP-sensitive inward rectifier potassium channel 11 ATP-binding cassette sub-family C member 9 Potassium channel subfamily K member 1 Sodium/calcium exchanger 1 Potassium/sodium hyperpolarization- activated cyclic nucleotide- gated channel 4 Sodium channel protein type 5 subunit alpha Beta-2- syntrophin Beta-1- syntrophin Alpha-1- syntrophin Voltage- dependent T-type calcium channel subunit alpha-1H Voltage- dependent T-type calcium channel subunit alpha-1G Sodium/calcium exchanger 1 cAMP-dependent protein kinase catalytic subunit alpha Inward rectifier potassium channel 2 Verapamil Ca+ Na+ Na+ K+ K+ K+ K+ K+ K+ K+ K+ K+ K+ K+ K+ K+ K+ K+ K+ Ca+ Ca+ Na+ Na+ Na+ Na+ K+ K+ Na+ Na+ Ca+ Ca+ Ca+ Ca+ Ca+ Na+ Na+ ATP H2O Ca+ ADP Pi Ca+ Verapamil Ca+ Troponin Troponin G-protein signalling cascade G-protein signalling cascade Muscle Contraction G protein- activated inward rectifier potassium channel 1 G protein- activated inward rectifier potassium channel 4 Potassium voltage-gated channel subfamily H member 2 Putative Dol-P- Glc:Glc(2)Man(9)GlcNAc(2)- PP-Dol alpha-1,2- glucosyltransferase Cardiac Muscle Striated Muscle Cell Nucleus Mitochondrion Myofibril Sarcoplasmic Reticulum Myofibril in Cardiac Myocyte Sarcolema Sarcoplasmic Reticulum Calcium binding to troponin displaces tropomyosin from the myosin binding sites on the actin filaments Myosin, with an ADP and phosphate attached, binds to actin to form a cross bridge. Myosin performs a powerstroke, drawing the actin filaments together. Many actin filaments pulled together at the same time leads to muscle contraction. Actin Filament Myosin Filament T-Tubule Depolarization Mitochondrion Single Sarcomere Functioning Unit Verapamil is typically administered intravenously as a racemic mixture Verapamil inhibits L-type calcium channels by binding to Cav1.2, part of their alpha-1 subunit Vascular Smooth Muscle Cell Verapamil prevents calcium ion influx by blocking calcium channels, which prevents smooth muscle contraction and relaxes the cells, leading to lower peripheral vascular resistance i.e. lower blood pressure. Verapamil can reduce angina, treat certain types of arrhythmia, and reduce hypertension by inhibiting calcium channels systemically and in the heart. As verapamil is lipophilic, it can diffuse into the cell. As well, there is some evidence that it can interact with organic cation transporters of the ABC family and alter P-glycoprotein efflux pump activity. Extracellular Space
Mitochondria Potassium Potassium Calcium TPM1 TPM2 ADRB1 PRKAR1A CACNA1C CACNA2D2 CACNB1 RYR2 CHRM2 PLN ATP2A2 KCNJ4 KCND3 KCNIP2 Unknown Unknown KCNQ1 KCNE1 KCNE2 ABCC8 KCNJ8 KCNJ11 Unknown KCNK1 SLC8A1 HCN4 SCN5A SNTB2 SNTB1 SNTA1 CACNA1H CACNA1G SLC8A1 PRKACA KCNJ2 Verapamil Calcium Sodium Sodium Potassium Potassium Potassium Potassium Potassium Potassium Potassium Potassium Potassium Potassium Potassium Potassium Potassium Potassium Potassium Potassium Calcium Calcium Sodium Sodium Sodium Sodium Potassium Potassium Sodium Sodium Calcium Calcium Calcium Calcium Calcium Sodium Sodium Adenosine triphosphate Water Calcium Adenosine diphosphate Phosphate Calcium Verapamil Calcium Troponin Troponin G-protein signalling cascade G-protein signalling cascade Muscle Contraction KCNJ3 KCNJ5 KCNH2 ALG10B
K+ K+ Ca+ TPM1 TPM2 ADRB1 PRKAR1A CACNA1C CACNA2D2 CACNB1 RYR2 CHRM2 PLN ATP2A2 KCNJ4 KCND3 KCNIP2 KCNQ1 KCNE1 KCNE2 ABCC8 KCNJ8 KCNJ11 KCNK1 SLC8A1 HCN4 SCN5A SNTB2 SNTB1 SNTA1 CACNA1H CACNA1G SLC8A1 PRKACA KCNJ2 Verpmil Ca+ Na+ Na+ K+ K+ K+ K+ K+ K+ K+ K+ K+ K+ K+ K+ K+ K+ K+ K+ Ca+ Ca+ Na+ Na+ Na+ Na+ K+ K+ Na+ Na+ Ca+ Ca+ Ca+ Ca+ Ca+ Na+ Na+ ATP H2O Ca+ ADP Pi Ca+ Verpmil Ca+ Troponi Troponi G-p s c G-p s c Mus Con KCNJ3 KCNJ5 KCNH2 ALG10B Cardiac Muscle Striated Muscle Cell Nucleus Mitochondrion Myofibril Sarcoplasmic Reticulum Myofibril in Cardiac Myocyte Sarcolema Sarcoplasmic Reticulum Calcium binding to troponin displaces tropomyosin from the myosin binding sites on the actin filaments Myosin, with an ADP and phosphate attached, binds to actin to form a cross bridge. Myosin performs a powerstroke, drawing the actin filaments together. Many actin filaments pulled together at the same time leads to muscle contraction. Actin Filament Myosin Filament T-Tubule Depolarization Mitochondrion Single Sarcomere Functioning Unit Verapamil is typically administered intravenously as a racemic mixture Verapamil inhibits L-type calcium channels by binding to Cav1.2, part of their alpha-1 subunit Vascular Smooth Muscle Cell Verapamil prevents calcium ion influx by blocking calcium channels, which prevents smooth muscle contraction and relaxes the cells, leading to lower peripheral vascular resistance i.e. lower blood pressure. Verapamil can reduce angina, treat certain types of arrhythmia, and reduce hypertension by inhibiting calcium channels systemically and in the heart. As verapamil is lipophilic, it can diffuse into the cell. As well, there is some evidence that it can interact with organic cation transporters of the ABC family and alter P-glycoprotein efflux pump activity. Extracellular Space
Mitochondria K+ K+ Ca2+ TPM1 TPM2 ADRB1 PRKAR1A CACNA1C CACNA2D2 CACNB1 RYR2 CHRM2 PLN ATP2A2 KCNJ4 KCND3 KCNIP2 KCNQ1 KCNE1 KCNE2 ABCC8 KCNJ8 KCNJ11 KCNK1 SLC8A1 HCN4 SCN5A SNTB2 SNTB1 SNTA1 CACNA1H CACNA1G SLC8A1 PRKACA KCNJ2 Verpmil Ca2+ Na+ Na+ K+ K+ K+ K+ K+ K+ K+ K+ K+ K+ K+ K+ K+ K+ K+ K+ Ca2+ Ca2+ Na+ Na+ Na+ Na+ K+ K+ Na+ Na+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Na+ Na+ ATP H2O Ca2+ ADP Pi Ca2+ Verpmil Ca2+ Troponi Troponi G-p s c G-p s c Mus Con KCNJ3 KCNJ5 KCNH2 ALG10B