Browsing Pathways

The monoamine oxidase is an enzyme that catalyzes the oxidative deamination of many amines like serotonin, norepinephrine, epinephrine, and dopamine. There are 2 isoforms of this protein: A and B. The first one is found in cells located in the periphery and breakdown serotonin, norepinephrine, epinephrine, dopamine, and tyramine. The second one, the B isoform, breakdowns phenylethylamine, norepinephrine, epinephrine, dopamine, and tyramine. This isoform is found in the extracellular tissues and mostly in the brain. The mechanism of action of the MAOIs is still not determined, it is thought that they act by increasing free serotonin and norepinephrine concentrations and/or by altering the concentrations of other amines in the CNS. mine oxidases are divided into two subfamilies based on the cofactor they contain. Amine oxidases catalyze oxidative deamination reactions, producing ammonia and an aldehyde. These enzymes are critical to both homeostatic and xenobiotic metabolic pathways and are involved in the biotransformation of aminergic neurotransmitters (such as catecholamines, histamine, and serotonin) as well as toxins and carcinogens in foods and the environment. The monoamine oxidases (MAOs) are well studied and have been targets for drug therapy for more than 60 years. MAOs are flavin-containing mitochondrial enzymes distributed throughout the body. In humans, two isoenzymes of MAO have been identified, encoded by two genes located on the X chromosome: MAO-A and MAO-B. Each isoenzyme can be distinguished by certain substrate specificities and anatomic distribution (Table 4.9), although MAO-A has the distinction of being the sole catecholamine metabolic enzyme in sympathetic neurons. In neural and other selective tissues, MAOs catalyze the first step in the degradation of catecholamines into their aldehyde intermediaries, which is further processed by catechol-O-methyltransferase. The ubiquity of biogenic amines and their central role in neural and cardiovascular function make MAOs highly relevant to clinical anesthesia. The interactions between MAO inhibitors and drugs commonly used in anesthesia have been well described. Although genetic polymorphisms in MAO genes exist and are of great interest in the fields of neurology and psychiatry, to date none have been identified that specifically concern the handling of anesthetic agents.

The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications like beta blockers, beta-2 (β2) agonists and alpha-2 (α2) agonists, which are used to treat high blood pressure and asthma, for example. The α2, on the other hand, couples to Gi, which causes a decrease in neurotransmitter release, as well as a decrease of cAMP activity resulting in smooth muscle contraction. Gi protein alpha subunit is a family of heterotrimeric G protein alpha subunits. This family is also commonly called the Gi/o (Gi /Go ) family or Gi/o/z/t family to include closely related family members. G alpha subunits may be referred to as Gi alpha, Gαi, or Giα. The general function of Gi/o/z/t is to activate intracellular signaling pathways in response to activation of cell surface G protein-coupled receptors (GPCRs). GPCRs function as part of a three-component system of receptor-transducer-effector. The transducer in this system is a heterotrimeric G protein, composed of three subunits: a Gα protein such as Giα, and a complex of two tightly linked proteins called Gβ and Gγ in a Gβγ complex. When not stimulated by a receptor, Gα is bound to GDP and to Gβγ to form the inactive G protein trimer. When the receptor binds an activating ligand outside the cell (such as a hormone or neurotransmitter), the activated receptor acts as a guanine nucleotide exchange factor to promote GDP release from and GTP binding to Gα, which drives dissociation of GTP-bound Gα from Gβγ. GTP-bound Gα and Gβγ are then freed to activate their respective downstream signaling enzymes. Gi proteins primarily inhibit the cAMP dependent pathway by inhibiting adenylyl cyclase activity, decreasing the production of cAMP from ATP, which, in turn, results in decreased activity of cAMP-dependent protein kinase. Therefore, the ultimate effect of Gi is the inhibition of the cAMP-dependent protein kinase. The Gβγ liberated by activation of Gi and Go proteins is particularly able to activate downstream signaling to effectors such as G protein-coupled inwardly-rectifying potassium channels (GIRKs). Contraction of smooth muscle is initiated by a Ca2+-mediated change in the thick filaments, whereas in striated muscle Ca2+ mediates contraction by changes in the thin filaments. In response to specific stimuli in smooth muscle, the intracellular concentration of Ca2+ increases, and this activator Ca2+ combines with the acidic protein calmodulin. This complex activates MLC kinase to phosphorylate the light chain of myosin (Fig. 1). Cytosolic Ca2+ is increased through Ca2+ release from intracellular stores (sarcoplasmic reticulum) as well as entry from the extracellular space through Ca2+ channels (receptor-operated Ca2+ channels). Agonists (norepinephrine, angiotensin II, endothelin, etc.) binding to serpentine receptors, coupled to a heterotrimeric G protein, stimulate phospholipase C activity. This enzyme is specific for the membrane lipid phosphatidylinositol 4,5-bisphosphate to catalyze the formation of two potent second messengers: inositol trisphosphate (IP3) and diacylglycerol (DG). The binding of IP3 to receptors on the sarcoplasmic reticulum results in the release of Ca2+ into the cytosol. DG, along with Ca2+, activates protein kinase C (PKC), which phosphorylates specific target proteins. There are several isozymes of PKC in smooth muscle, and each has a tissue-specific role (e.g., vascular, uterine, intestinal, etc.). In many cases, PKC has contraction-promoting effects such as phosphorylation of L-type Ca2+ channels or other proteins that regulate cross-bridge cycling.

Gq protein alpha subunit is a family of heterotrimeric G protein alpha subunits. This family is also commonly called the Gq/11 (Gq/G11) family or Gq/11/14/15 family to include closely related family members. G alpha subunits may be referred to as Gq alpha, Gαq, or Gqα. Gq proteins couple to G protein-coupled receptors to activate beta-type phospholipase C (PLC-β) enzymes. PLC-β in turn hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to diacyl glycerol (DAG) and inositol trisphosphate (IP3). IP3 acts as a second messenger to release stored calcium into the cytoplasm, while DAG acts as a second messenger that activates protein kinase C (PKC). Depending on the Gα subunit involved in the complex, the most well-known G-proteins are qualified as Gi, Gs, or Gq. They signal through different pathways. Gq proteins rely on enzymes of the phospholipase C family (PLC), while Gs and Gi proteins respectively stimulate and inhibit adenylate cyclase (AC) and thus act upon the amount of cytosolic cAMP. Contraction of smooth muscle is initiated by a Ca2+-mediated change in the thick filaments, whereas in striated muscle Ca2+ mediates contraction by changes in the thin filaments. In response to specific stimuli in smooth muscle, the intracellular concentration of Ca2+ increases, and this activator Ca2+ combines with the acidic protein calmodulin. This complex activates MLC kinase to phosphorylate the light chain of myosin (Fig. 1). Cytosolic Ca2+ is increased through Ca2+ release from intracellular stores (sarcoplasmic reticulum) as well as entry from the extracellular space through Ca2+ channels (receptor-operated Ca2+ channels). Agonists (norepinephrine, angiotensin II, endothelin, etc.) binding to serpentine receptors, coupled to a heterotrimeric G protein, stimulate phospholipase C activity. This enzyme is specific for the membrane lipid phosphatidylinositol 4,5-bisphosphate to catalyze the formation of two potent second messengers: inositol trisphosphate (IP3) and diacylglycerol (DG). The binding of IP3 to receptors on the sarcoplasmic reticulum results in the release of Ca2+ into the cytosol. DG, along with Ca2+, activates protein kinase C (PKC), which phosphorylates specific target proteins. There are several isozymes of PKC in smooth muscle, and each has a tissue-specific role (e.g., vascular, uterine, intestinal, etc.). In many cases, PKC has contraction-promoting effects such as phosphorylation of L-type Ca2+ channels or other proteins that regulate cross-bridge cycling. Muscarinic receptors that use Gq protein signalling to contract smooth muscles include the M3 receptors. The M3 muscarinic receptors are located at many places in the body. They are located in the smooth muscles of the blood vessels, as well as in the lungs. Because the M3 receptor is Gq-coupled and mediates an increase in intracellular calcium, it typically causes contraction of smooth muscle, such as that observed during bronchoconstriction and bladder voiding.

Muscle contractions occur when the myocyte is depolarized enough for an action potential to occur. Depolarization is caused by acetylcholine released from the adjacent motor neuron, which activates nicotinic acetylcholine receptors and opens the sodium/potassium channel. The fast influx of sodium and slow efflux of potassion trigger the action potential. This action potential activates L-type voltage-dependent calcium channels on the membrane and ryanodine receptors on the sarcoplasmic reticulum, both which cause calcium ions to be released into the cytosol. In smooth muscle, ionic calcium induces muscle contraction by binding to and activating myosin light chain kinase, while in striated muscle contraction results from ionic calcium binding to and activating troponin C.

try

PASSIVE TARGETING OF DRUGS TO THE CANCER