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Adenylate cyclase type 10 Myosin light chain kinase, smooth muscle PKA complex PKA complex Protein kinase C D(2) dopamine receptor D(2) dopamine receptor Myosin LC-P Myosin light chain 3 Inositol 1,4,5- trisphosphate receptor type 1 Voltage- dependent L-type calcium channel subunit beta-1 Voltage- dependent L-type calcium channel subunit alpha-1C Voltage- dependent P/Q-type calcium channel subunit alpha-1A Voltage- dependent L-type calcium channel subunit beta-1 Voltage- dependent calcium channel subunit alpha-2/delta-2 Sodium- dependent dopamine transporter Synaptic vesicular amine transporter Myosin light chain phosphatase Calmodulin Intermediate conductance calcium- activated potassium channel protein 4 Phospholipase C 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 Aromatic-L- amino-acid decarboxylase Tyrosine 3-monooxygenase Calmodulin Voltage- dependent calcium channel subunit alpha-2/delta-1 Dopamine Ca+ Domperidone Ca+ Ca+ K+ K+ Ca+ K+ K+ Ca+ Dopamine Dopamine Domperidone ATP cAMP Inositol 1,4,5-trisphosphate Phosphatidylinositol 4,5-bisphosphate Diacylglycerol L-Dopa CO2 L-Tyrosine Tetrahydrobiopterin O2 Dihydrobiopterin H2O Na+ Na+ Pi Pi Pi Pi Calcium Pyridoxal 5'-phosphate Ca+ Muscle Contraction Muscle Relaxation Gi Signaling Cascade Gi Protein Signaling Cascade Magnesium Calcium Fe2+ Manganese Sarcoplasmic Reticulum Cytosol Stomach Smooth Muscle Cell Activated PKA can phosphorylate calcium activated potassium channels causing potassium efflux and promoting hyperpolarization. Activated PKA phosphorylates the IP3 receptor to reduce its affinity for IP3. Activated PKA phosphorylates phospholipase C. There is an overall decrease in calcium levels in the cytosol. Decreased calcium is unable to bind readily to calmodulin. The inhibition of myosin light chain kinase prevents the synthesis of Myosin LC-P which leads to a high concentration of myosin light chain and muscle relaxation. Myosin binds to actin causing the sarcomere filaments to key into each other resulting in muscle contractility. Activates ATP-sensitive potassium channels via cAMP mediated phosphorylation. Actin Filament Myosin Filament Since the receptor isn't activated, adenylyl cyclase is no longer inhibited allowing for cAMP production D2 receptors activate Gi protein signalling which inhibits adenylyl cyclase Cytosol Postsynaptic Neuron Presynaptic Neuron Cytosol Synaptic Vesicle Synapse Domperidone is a prokinetic agent. It increases gastric motility and increases the release of ACh from the GI tract ↓ nausea and vomiting Brain Blood vessel passive diffusion Dopamine receptors in the chemoreceptor trigger zone (area postrema) is stimulated to cause nausea and vomiting Domperidone acts as an antagonist to D2 receptors present in the vagus nerves from brain to gut Vomiting Centre (medulla) Chemoreceptor trigger zone Domperidone blocks dopamine receptors in the chemoreceptor trigger zone