Browsing Pathways

H1-antihistamines interfere with the agonist action of histamine at the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. Wakefulness is regulated by histamine in the tuberomammillary nucleus, a part of the hypothalamus. Histidine is decarboxylated into histamine in the neuron. Histamine is transported into synaptic vesicles by a monoamine transporter then released into the synapse. Normally histamine would activate the H1 histamine receptor on the post-synaptic neuron in the tuberomammillary nucleus. Doxylamine inhibits the H1 histamine receptor, preventing the depolarization of the post-synaptic neuron. This prevents the wakefulness signal from being sent to the major areas of the brain, causing sleepiness.

The Gs alpha subunit (Gαs, Gsα) is a subunit of the heterotrimeric G protein Gs that stimulates the cAMP-dependent pathway by activating adenylyl cyclase. Gsα is a GTPase that functions as a cellular signaling protein. Gsα is the founding member of one of the four families of heterotrimeric G proteins, defined by the alpha subunits they contain: the Gαs family, Gαi/Gαo family, Gαq family, and Gα12/Gα13 family. The Gs-family has only two members: the other member is Golf, named for its predominant expression in the olfactory system. In humans, Gsα is encoded by the GNAS complex locus, while Golfα is encoded by the GNAL gene. The general function of Gs 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 Gsα, 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. In particular, GTP-bound, activated Gsα binds to adenylyl cyclase to produce the second messenger cAMP, which in turn activates the cAMP-dependent protein kinase (also called Protein Kinase A or PKA). Cellular effects of Gsα acting through PKA are described here. Although each GTP-bound Gsα can activate only one adenylyl cyclase enzyme, amplification of the signal occurs because one receptor can activate multiple copies of Gs while that receptor remains bound to its activating agonist, and each Gsα-bound adenylyl cyclase enzyme can generate substantial cAMP to activate many copies of PKA. H2 receptors are positively coupled to adenylate cyclase via Gs alpha subunit. It is a potent stimulant of cAMP production, which leads to activation of protein kinase A. PKA functions to phosphorylate certain proteins, affecting their activity. Activation of the H2 receptor results in the following physiological responses: stimulation of gastric acid secretion (Target of anti-histaminergics (H2 receptors) for peptic ulcer disease and GERD), smooth muscle relaxation (Experimental histamine H2 receptor agonist used for asthma and COPD), and vasodilation – PKA activity causes phosphorylation of MLCK, decreasing its activity, resulting in MLC of myosin being dephosphorylated by MLCP and thus inhibiting contraction. The smooth muscle relaxation leads to vasodilation.

G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their activity is regulated by factors that control their ability to bind to and hydrolyze guanosine triphosphate (GTP) to guanosine diphosphate (GDP). When they are bound to GTP, they are 'on', and, when they are bound to GDP, they are 'off'. G proteins belong to the larger group of enzymes called GTPases. Heterotrimeric G proteins located within the cell are activated by G protein-coupled receptors (GPCRs) that span the cell membrane. Signaling molecules bind to a domain of the GPCR located outside the cell, and an intracellular GPCR domain then in turn activates a particular G protein. Some active-state GPCRs have also been shown to be "pre-coupled" with G proteins, whereas in other cases a collision coupling mechanism is thought to occur. The G protein triggers a cascade of further signaling events that finally results in a change in cell function. G protein-coupled receptors and G proteins working together transmit signals from many hormones, neurotransmitters, and other signaling factors. G proteins regulate metabolic enzymes, ion channels, transporter proteins, and other parts of the cell machinery, controlling transcription, motility, contractility, and secretion, which in turn regulate diverse systemic functions such as embryonic development, learning and memory, and homeostasis. Receptor-activated G proteins are bound to the inner surface of the cell membrane. They consist of the Gα and the tightly associated Gβγ subunits. There are four main families of Gα subunits: Gαs (G stimulatory), Gαi (G inhibitory), Gαq/11, and Gα12/13. They behave differently in the recognition of the effector molecule, but share a similar mechanism of activation. When a ligand activates the G protein-coupled receptor, it induces a conformational change in the receptor that allows the receptor to function as a guanine nucleotide exchange factor (GEF) that exchanges GDP for GTP. The GTP (or GDP) is bound to the Gα subunit in the traditional view of heterotrimeric GPCR activation. This exchange triggers the dissociation of the Gα subunit (which is bound to GTP) from the Gβγ dimer and the receptor as a whole. Both Gα-GTP and Gβγ can then activate different signaling cascades (or second messenger pathways) and effector proteins, while the receptor is able to activate the next G protein. 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. 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). Gi and Go proteins are substrates for pertussis toxin, produced by Bordetella pertussis, the infectious agent in whooping cough. Pertussis toxin is an ADP-ribosylase enzyme that adds an ADP-ribose moiety to a particular cysteine residue in Giα and Goα proteins, preventing their coupling to and activation by GPCRs, thus turning off Gi and Go cell signaling pathways. Activation of Gi proteins in vascular smooth muscle cells often results in vasoconstriction. This is because reduced cAMP levels and decreased PKA activity lead to increased intracellular calcium concentrations, promoting smooth muscle contraction. In summary, while Gi signaling plays a role in both smooth and cardiac muscle tissues, its specific effects and functions differ due to the distinct roles and regulatory mechanisms of these muscles. In smooth muscle, Gi signaling often leads to vasoconstriction, while in cardiac muscle, it primarily regulates heart rate through the inhibition of If channels in the SA node, resulting in a negative chronotropic effect.

Tyrosine kinase inhibitors (TKIs) block chemical messengers (enzymes) called tyrosine kinases. Tyrosine kinases help to send growth signals in cells, so blocking them stops the cell growing and dividing. Cancer growth blockers can block one type of tyrosine kinase or more than one type. Tyrosine kinase inhibitors (TKIs) inhibit corresponding kinases from phosphorylating tyrosine residues of their substrates and then block the activation of downstream signaling pathways. Tyrosine kinase enzymes (TKs) can be categorized into receptor tyrosine kinases (RTKs), non-receptor tyrosine kinases (NRTKs), and a small group of dual-specificity kinases (DSK) which can phosphorylate serine, threonine, and tyrosine residues. RTKs are transmembrane receptor that includes vascular endothelial growth factor receptors (VEGFR), platelet-derived growth factor receptors (PDGFR), insulin receptor (InsR) family, and the ErbB receptor family, which includes epidermal growth factor receptors (EGFR) and the human epidermal growth factor receptor-2 (HER2). NRTKs are cytoplasmic proteins that consist of nine families, including Abl, Ack, Csk, Fak, Fes/Fer, Jak, Src, Syk/Zap70, and Tec, with the addition of Brl/Sik, Rak/Frk, Rlk/Txk, and Srm, which fall outside the nine defined families. The most notable example of DSKs is the mitogen-activated protein kinase kinases (MEKs), which are principally involved in the MAP pathways. Kinase inhibitors are either irreversible or reversible. The irreversible kinase inhibitors tend to covalently bind and block the ATP site resulting in irreversible inhibition. The reversible kinase inhibitors can further subdivide into four major subtypes based on the confirmation of the binding pocket as well as the DFG motif. Different binding modes of TKIs include Type I inhibitors: competitively bind to the ATP-binding site of active TKs. The arrangement of the DFG motif in type I inhibitors has the aspartate residue facing the catalytic site of the kinase. Type II inhibitors: bind to inactive kinases, usually at the ATP-binding site. The DFG motif in type II inhibitors protrudes outward away from the ATP-binding site. Due to the outward rotation of the DFG motif, many type II inhibitors can also exploit regions adjacent to the ATP-binding site that would otherwise be inaccessible. Type III inhibitors: do not interact with the ATP-binding pocket. Type III inhibitors exclusively bind to allosteric pockets adjacent to the ATP-binding region. Type IV inhibitors: bind allosteric sites far removed from the ATP-binding pocket. Type V inhibitors: refer to a proposed subset of kinase inhibitors that exhibit multiple binding modes

Coagulation of the blood can be initiation from two different pathways that both result in formation of thrombin which converts blood soluble fibrinogen into the insoluble fibrin clot at the site of injury. The intrinsic pathway is activated by trauma inside vasculature and is activated by platelets, exposed endothelium and collagen. In the liver the coagulation factors VII, IX, and X are produced there as they are vitamin K-dependent proteins. Exposed collagen from broken vessels binds to factor XII activating it to XIIa which converts prekallikrein and factor XI to kallikrein and factor XIa respectively. The extrinsic pathway is activated by the external trauma of blood escaping the vasculature system as the membrane-bound protein tissue factor (TF) is exposed to factors VII or VIIa in the plasma forming a strong activator complex. This activator complex of VIIa and TF converts factor X to the activated form. Both the intrinsic and extrinsic pathways lead to the prothrombinase complex as both pathways activate factor X, an important player in the complex. The prothrombinase complex converts prothrombin to thrombin further allowing the conversion of insoluble fibrinogen into fibrin. Fibrin at first is loose and unstable and is stabilized by coagulation factor XIIIa which cross-links them to form the fibrin clot/mesh that stops blood leaking from the vasculature system. The activated proteins are colored orange.

Endogenous incretins such as such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are hormones regulating insulin secretion and glucose metabolism in mammals. Incretin acts by stimulating β cells of the pancreas to release more insulin in the blood. GIP is secreted by the enteroendocrine K-cells that are present in high density in the duodenum and upper jejunum but are present throughout the small intestine. Oral ingestion and subsequent absorption of nutrients such as glucose, high amounts of amino acids, and long-chain fatty acids trigger the secretion of GIP. Glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide (GIP), both incretin hormones inactivated by dipeptidyl peptidase-4 (DPP-4), stimulate insulin secretion after an oral glucose load via the incretin effect. In type 2 diabetes, this process can become blunted or even be absent; however, the utilization of pharmacological levels of GLP-1 can revive insulin excretion. The benefits of this form of therapy to treat type 2 diabetes include delayed gastric emptying and inhibiting the production of glucagon from pancreatic alpha cells if blood sugar levels are high. Furthermore, GLP-1 receptor agonists can decrease pancreatic beta-cell apoptosis while promoting their proliferation. GIP acts on class-II G-protein coupled receptors. The signaling mechanism for these receptors primarily involves the activation of adenylate cyclase/protein kinase A as well as phospholipase C/protein C cascades. High levels of GIP receptors get expressed in the beta cells of the pancreatic islets. Binding of GIP to its receptor increases the intracellular cAMP levels with a downstream increase in calcium ion concentration and exocytosis of insulin. GIP is rapidly inactivated by the ubiquitous enzyme dipeptidyl peptidase 4 (DPP-4), which is the same enzyme that cleaves GLP-1. However, the inactivation of GIP occurs at a slower rate than GLP-1, giving GIP a half-life of 5 to 7 minutes. DPP-4 cleaves alanine and proline residues in position 2 of the N-terminus in peptide chains. Thus, the substitution of L-alanine for D-alanine residue at position 2 of GIP makes it resistant to the action of DPP-4 and enhances its incretin effect. Incretins binds to the ATP-sensitive potassium channels on the pancreatic cell surface. This binding causes the reduction of the potassium conductance and, in consequence, the depolarization of the membrane. This depolarization stimulates calcium ion influx through voltage-sensitive calcium channels, raising intracellular concentrations of calcium ions, which results in the secretion (exocytosis) of insulin. These incretins are released in response to food intake and regulate both basal insulin secretion and meal-stimulated insulin release.

Angiotensin is a peptide hormone that causes vasoconstriction and a subsequent increase in blood pressure. It is part of the renin-angiotensin system, which is a major target for drugs that lower blood pressure. Angiotensin also stimulates the release of aldosterone, another hormone, from the adrenal cortex. Aldosterone promotes sodium retention in the distal nephron, in the kidney, which also drives blood pressure up. (Wikipedia)