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Ca+ Tropomyosin alpha-1 chain Tropomyosin beta chain 5- hydroxytryptamine receptor 2A 5- hydroxytryptamine receptor 2B 5- hydroxytryptamine receptor 1A Voltage- depenent L-type calcium channel Voltage- depenent L-type calcium channel Voltage- depenent L-type calcium channel Ryanodine receptor 2 Sodium/calcium exchanger 1 Voltage-gated T-type calcium channel (ICaT) Voltage-gated T-type calcium channel (ICaT) 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 Synaptic vesicular amine transporter Sodium- dependent serotonin transporter Tryptophan 5-hydroxylase 1 Aromatic-L- amino-acid decarboxylase Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 cAMP-dependent protein kinase catalytic subunit alpha Ca+ Serotonin Serotonin Methysergide Methysergide Methysergide Ca+ Ca+ Ca+ Na+ Na+ Ca+ Ca+ Ca+ Ca+ Serotonin Methysergide L-Tryptophan Tetrahydrobiopterin O2 5-Hydroxy-L-tryptophan 4a-Hydroxytetrahydrobiopterin CO2 Na+ Na+ ATP H2O Ca+ ADP Pi Ca+ Fe2+ Pyridoxal 5'-phosphate Ca+ Troponin Troponin Muscle Relaxation GCPR signalling pathway GCPR signalling pathway Vascular endothelial cells Sarcoplasmic Reticulum Normally, calcium binding to troponin displaces tropomyosin from the myosin binding sites on the actin filaments. Low concentrations of calcium disallow this from occurring. Myosin and actin filaments slide further away from each other leading to muscle relaxation. Actin Filament Myosin Filament The 5-HT2 receptor is coupled to Methysergide and antagonizing this receptor results in the G protein signalling cascade not being activated. The G-protein signalling cascade activates protein kinase which activates calcium channels on the membrane, resulting in calcium influx. Low calcium cannot activate the ryanodine receptor on the sarcoplasmic reticulum. Cytosol Since calcium is linked to activation of muscle contraction. Reducing cytosolic calcium levels reduces muscle contraction Methysergide acts by narrowing blood vessels in the brain and reduces blood flow thereby alleviating migraine symptoms Synaptic Vesicle Cytosol Cytosol Presynaptic Neuron Postsynaptic Neuron Synapse ↓ migraine and vascular headaches Serotonin is synthesized at the raphei nuclei and stored in synaptic vesicles at the nerve terminal Methysergide is an antagonist on 5-HT2A, 5-HT2B and 5-HT2C receptors and exhibits vasoconstriction of blood vessels and agonist at 5-HT1A receptors Brain Raphei nuclei producing serotonergic neurons Blood vessel - blood brain barrier passive diffusion Methysergide is administered orally
Calcium TPM1 TPM2 HTR2A HTR2B HTR1A CACNA1C CACNA2D2 CACNB1 RYR2 SLC8A1 CACNA1H CACNA1G CACNA1A CACNB1 CACNA2D2 SLC18A2 SLC6A4 TPH1 DDC ATP2A2 PRKACA Calcium Serotonin Serotonin Methysergide Methysergide Methysergide Calcium Calcium Calcium Sodium Sodium Calcium Calcium Calcium Calcium Serotonin Methysergide L-Tryptophan Tetrahydrobiopterin Oxygen 5-Hydroxy-L- tryptophan 4a- Hydroxytetrahydrobiopterin Carbon dioxide Sodium Sodium Adenosine triphosphate Water Calcium Adenosine diphosphate Phosphate Calcium Calcium Troponin Troponin Muscle Relaxation GCPR signalling pathway GCPR signalling pathway
Ca+ TPM1 TPM2 HTR2A HTR2B HTR1A CACNA1C CACNA2D2 CACNB1 RYR2 SLC8A1 CACNA1H CACNA1G CACNA1A CACNB1 CACNA2D2 SLC18A2 SLC6A4 TPH1 DDC ATP2A2 PRKACA Ca+ 5-HT 5-HT Methyse Methyse Methyse Ca+ Ca+ Ca+ Na+ Na+ Ca+ Ca+ Ca+ Ca+ 5-HT Methyse Trp BH4 O2 5-HTP 4aHtHbp CO2 Na+ Na+ ATP H2O Ca+ ADP Pi Ca+ Fe2+ Pyr-5'P Ca+ Troponi Troponi Mus Rel GC si p GC si p Vascular endothelial cells Sarcoplasmic Reticulum Normally, calcium binding to troponin displaces tropomyosin from the myosin binding sites on the actin filaments. Low concentrations of calcium disallow this from occurring. Myosin and actin filaments slide further away from each other leading to muscle relaxation. Actin Filament Myosin Filament The 5-HT2 receptor is coupled to Methysergide and antagonizing this receptor results in the G protein signalling cascade not being activated. The G-protein signalling cascade activates protein kinase which activates calcium channels on the membrane, resulting in calcium influx. Low calcium cannot activate the ryanodine receptor on the sarcoplasmic reticulum. Cytosol Since calcium is linked to activation of muscle contraction. Reducing cytosolic calcium levels reduces muscle contraction Methysergide acts by narrowing blood vessels in the brain and reduces blood flow thereby alleviating migraine symptoms Synaptic Vesicle Cytosol Cytosol Presynaptic Neuron Postsynaptic Neuron Synapse ↓ migraine and vascular headaches Serotonin is synthesized at the raphei nuclei and stored in synaptic vesicles at the nerve terminal Methysergide is an antagonist on 5-HT2A, 5-HT2B and 5-HT2C receptors and exhibits vasoconstriction of blood vessels and agonist at 5-HT1A receptors Brain Raphei nuclei producing serotonergic neurons Blood vessel - blood brain barrier passive diffusion Methysergide is administered orally
Ca2+ TPM1 TPM2 HTR2A HTR2B HTR1A CACNA1C CACNA2D2 CACNB1 RYR2 SLC8A1 CACNA1H CACNA1G CACNA1A CACNB1 CACNA2D2 SLC18A2 SLC6A4 TPH1 DDC ATP2A2 PRKACA Ca2+ 5-HT 5-HT Methyse Methyse Methyse Ca2+ Ca2+ Ca2+ Na+ Na+ Ca2+ Ca2+ Ca2+ Ca2+ 5-HT Methyse Trp BH4 O2 5-HTP 4aHtHbp CO2 Na+ Na+ ATP H2O Ca2+ ADP Pi Ca2+ Ca2+ Troponi Troponi Mus Rel GC si p GC si p