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Guanylate cyclase soluble subunit beta-2 Guanylate cyclase soluble subunit beta-1 Voltage- dependent L-type calcium channel subunit beta-1 Guanylate cyclase soluble subunit alpha-2 Guanylate cyclase soluble subunit alpha-3 cGMP-dependent protein kinase 1 cGMP-dependent protein kinase 2 Voltage- dependent L-type calcium channel subunit alpha-1C Voltage- dependent calcium channel subunit alpha-2/delta-2 Sarcoplasmic/endoplasmic reticulum calcium ATPase 1 Ryanodine receptor 2 Nitric oxide synthase, endothelial Myosin light chain kinase, smooth muscle Myosin light chain 3 Myosin LC-P Myosin light chain phosphatase Calmodulin-1 Calmodulin-1 Calmodulin-1 Calmodulin-1 Potassium voltage-gated channel subfamily D member 2 Kv channel- interacting protein 2 NO Cyclic GMP Caffeine K+ K+ Ca+ Ca+ Ca+ Ca+ Ca+ Ca+ NO GTP PPi L-Arginine H+ NADPH O2 H2O Citrulline NADP Heme FAD Flavin Mononucleotide Tetrahydrobiopterin Ca+ Ca+ Muscle Relaxation Calcium Magnesium Manganese Myosin and actin are unbound allowing the filaments to slide further apart, resulting in muscle relaxation Myocyte Cytosol The activation of potassium channels leads to an efflux of potassium which causes hyperpolarization of the myocyte Smooth muscle relaxation causes vasodilation of the arteries and veins Hyperpolarization The dephosphoylation of myosin light chain-phosphatase causes myosin to unbind from actin, causing muscle relaxation. The low concentration of calcium means it cannot bind to calmodulin. This prevents calmodulin from activating myosin light chain kinase which leads to an inhibitory effect and prevents muscle contraction. cGMP-dependent protein kinase also activates sarcoplasmic reticulum calcium ATPase which causes the reuptake of cytosolic calcium into the sarcoplasmic reticulum, further lowering the concentration of cytosolic calcium. The hyperpolarization of the muscle cell inhibits voltage-gates calcium channels, which are also inhibited by protein kinase. This prevents calcium from entering the myocyte. This leads to a low concentration of cytosolic calcium. Sarcoplasmic Reticulum Endothelial Cell Cytosol Endoplasmic Reticulum Nitric oxide diffuses through the layers to the smooth muscle cells and activates guanylate cyclase Caffeine activates Ryanodine receptors in the endoplasmic retiuclum of endothelial cells. This causes calcium to enter the cytosol. Calcium binds to calmodulin which activates nitric oxide synthase to catalyze the synthesis of nitric oxide. Media The exact mechanism of caffeine activating ryanodine receptors is unknown. In the head and neck caffeine reduces the production of nitric oxide through antagonism of the adenosine A2A receptor, which is known to increase production of nitric oxide. Myosin Actin Vasodilation
Endoplasmic Reticulum GUCY1B2 GUCY1B3 CACNB1 GUCY1A2 GUCY1A3 PRKG1 PRKG2 CACNA1C