Pathways

The branched chain amino acid (BCAA) leucine is able to signal transduction pathways that modulate translation initiation for protein synthesis in skeleton muscles. In the presence of leucine, hyperphosphorylation of 4E-BP1 causes its affinity for eIF4E to be lowered. This allows eIF4F protein complexes to recognize, unfold and guide the mRNA to the 43S preinitiation complex thereby increasing translation initiation. In addition, leucine has a transient affect on the release of insulin and/or enhances sensitivity of muscle cells to insulin. A culmination of both signals at the mammalian target of rapamycin (mTOR) and perhaps other signaling, such as PKCδ, are needed for maximum translation initiation to occur.

The branched chain amino acid (BCAA) leucine is able to signal transduction pathways that modulate translation initiation for protein synthesis in skeleton muscles. In the presence of leucine, hyperphosphorylation of 4E-BP1 causes its affinity for eIF4E to be lowered. This allows eIF4F protein complexes to recognize, unfold and guide the mRNA to the 43S preinitiation complex thereby increasing translation initiation. In addition, leucine has a transient affect on the release of insulin and/or enhances sensitivity of muscle cells to insulin. A culmination of both signals at the mammalian target of rapamycin (mTOR) and perhaps other signaling, such as PKCδ, are needed for maximum translation initiation to occur.

The branched chain amino acid (BCAA) leucine is able to signal transduction pathways that modulate translation initiation for protein synthesis in skeleton muscles. In the presence of leucine, hyperphosphorylation of 4E-BP1 causes its affinity for eIF4E to be lowered. This allows eIF4F protein complexes to recognize, unfold and guide the mRNA to the 43S preinitiation complex thereby increasing translation initiation. In addition, leucine has a transient affect on the release of insulin and/or enhances sensitivity of muscle cells to insulin. A culmination of both signals at the mammalian target of rapamycin (mTOR) and perhaps other signaling, such as PKCδ, are needed for maximum translation initiation to occur.

Leukotriene C4 synthetase deficiency is caused by a defect in the enzyme leukotriene C4 synthetase (LTC4S). This enzyme catalyzes the synthesis of leukotriene C4 (LTC4) through conjugation of LTA4 with reduced glutathione (GSH), which is synthesized by glutathione synthetase. Leukotriene C4 and its receptor-binding metabolites LTD4 and LTE4 are cysteinyl leukotrienes that are potent lipid mediators of tissue inflammation. In general, leukotrienes are potent proinflammatory mediators synthesized from membrane-derived arachidonic acid after activation of certain granulocytes. A defect in LTC4 results in decreased concentrations of cysteinyl leukotrienes LTC4, LTD4 and LTE4 in plasma, spinal fluid and urine. Symptoms include early death, failure to thrive, motor retardation, microcephaly, and progressive neurological defect.

Leukotriene C4 synthetase deficiency is caused by a defect in the enzyme leukotriene C4 synthetase (LTC4S). This enzyme catalyzes the synthesis of leukotriene C4 (LTC4) through conjugation of LTA4 with reduced glutathione (GSH), which is synthesized by glutathione synthetase. Leukotriene C4 and its receptor-binding metabolites LTD4 and LTE4 are cysteinyl leukotrienes that are potent lipid mediators of tissue inflammation. In general, leukotrienes are potent proinflammatory mediators synthesized from membrane-derived arachidonic acid after activation of certain granulocytes. A defect in LTC4 results in decreased concentrations of cysteinyl leukotrienes LTC4, LTD4 and LTE4 in plasma, spinal fluid and urine. Symptoms include early death, failure to thrive, motor retardation, microcephaly, and progressive neurological defect.

Leukotriene C4 synthetase deficiency is caused by a defect in the enzyme leukotriene C4 synthetase (LTC4S). This enzyme catalyzes the synthesis of leukotriene C4 (LTC4) through conjugation of LTA4 with reduced glutathione (GSH), which is synthesized by glutathione synthetase. Leukotriene C4 and its receptor-binding metabolites LTD4 and LTE4 are cysteinyl leukotrienes that are potent lipid mediators of tissue inflammation. In general, leukotrienes are potent proinflammatory mediators synthesized from membrane-derived arachidonic acid after activation of certain granulocytes. A defect in LTC4 results in decreased concentrations of cysteinyl leukotrienes LTC4, LTD4 and LTE4 in plasma, spinal fluid and urine. Symptoms include early death, failure to thrive, motor retardation, microcephaly, and progressive neurological defect.

Levacetylmethadol, also known as Levomethadyl acetate, Levacetylmethadol is a narcotic analgesic with a long onset and duration of action. It was withdrawn from the European Union due to its high risk of QT interval prolongation. Its production also ceased in the United States. Levacetylmethadol is an agonist of mu-opioid receptors. It is also an antagonist of neuronal acetylcholine receptors with unknown pharmacological effects. Levacetylmethadol binds to mu opioid receptors on presynaptic neuron membranes, stimulating the exchange of GTP for GDP on the G-protein complex. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine, and noradrenaline is inhibited. Opioids close N-type voltage-operated calcium channels and open calcium-dependent inwardly rectifying potassium channels. This results in hyperpolarization and reduced neuronal excitability. Morphine acts at A delta and C pain fibres in the dorsal horn of the spinal cord. By decreasing neurotransmitter action there is less pain transmittance into the spinal cord. This leads to less pain perception.

Levallorphan (also known as Lorfan and Naloxifan) is a type of medication that can be used for treating drug overdoses and respirotry depression. Levallorphan can bind to mu-type opioid receptor and kappa-type opioid receptor on neuron of central nerves system (CNS). Effects of opioids such as respiratory depression, hypotension and sedation can be prevented or reversed by levallorphan. Levallorphan can also be used for treating pentazocine which is a type of psychotomimetic and dysphoric effects of agonist-antagonists.

Levallorphan is an opioid antagonist similar to nalexone, which also has some agonist properties. Levallorphan is used to treat respiratory depression caused by opioid overdose. The partial agonist properties of levallorphan allow if to prevent respiratory depression while also maintaining some of the euphoria induced by the opioids. It mainly targets the mu opioid receptor, however some research indicates it has effects on the kappa opioid receptor, different from the mu opioid receptor which allow it to prevent respiratory depression while also maintaining euphoria. Respiratory depression is thought to occurs due to inhibition of the PreBötzinger complex in the medulla of the brainstem where breathing rhythm is controlled by CO2 concentrations.. Opioids inhibit this, causing respiratory depression through hyperpolarization, which lowers the sensitivity to CO2. However, Levallorphan has been found to increase respiratory depression caused by alcohol or other drugs. Levallorphan is speculated to antagonize Mu opioid receptors on post synaptic neurons in the PreBötzinger complex in the brainstem. This inhibits the exchange of GTP for GDP which is required to activate the G-protein complex. This prevents the Gi subunit of the mu opioid receptor from inhibiting adenylate cyclase, which can therefore continue to catalyze ATP into cAMP. With the mu opioid receptor unable to inhibit adenylate cyclase, it is able to synthesize cAMP which increases the excitability the PreBötzinger Complex in the brain which increases respiration. The inhibition of Mu-type opioid receptors also prevents the Gi subunit of the mu opioid receptor from activating the inwardly rectifying potassium channel increasing K+ conductance which would cause hyperpolarization. Levallorphan also prevents the gamma subunit of the mu opioid receptor from inhibiting the N-type calcium channels on the neuron. This allows calcium to enter the neuron and depolarize. Levallorphan antagonizing the mu-opioid receptor prevents hyperpolarization which would cause respiratory depression and hypoxia. This, therefore, leads to regulation of breathing in those with opioid-induced respiratory depression.