Pathways

about pi3K also known as phosphotidylinositol 3 Kinase involved in AKT signalling and is the main activator of PIP2.

Pibrentasvir is a direct acting antiviral agent and Hepatitis C virus (HCV) nonstructural protein 5A inhibitor that targets the the viral RNA replication and viron assembly. In combination with Glecaprevir. Hepatitis C virus lipoviroparticles enter target hepatocytes via receptor-mediated endocytosis. The lipoviroparticles attach to LDL-R and SR-B1, and then the virus binds to CD81 and subsequently claudin-1 and occludin, which mediate the late steps of viral entry. The virus is internalized by clathrin-dependent endocytosis. RNA is released from the mature Hepatitis C virion and translated at the rough endoplasmic reticulum into a single Genome polyprotein. The genome polyprotein is cleaved by host and viral proteases into 10 viral proteins. The nucleocapsid protein core and the two envelope proteins E1 and E2 form the N terminus of the polyprotein and are the structural components of HCV virions. The precursor also gives rise to the viroporin p7 and six non-structural (NS) proteins. Pibrentasvir is an inhibitor of the Hepatitis C Virus (HCV) Nonstructural protein 5A, which is required for viral RNA replication and assembly of HCV virions. The exact mechanism of this protein is unknown. NS5A inhibitors compete with RNA for binding at this site. Viral RNA replication complexes localize to lipid raft-containing, detergent-resistant membranes created by the viral protein NS4B.ding site is exposed. For full viral replication and maturation, replication complexes need to be in close proximity to lipid droplets, which requires the protein nonstructural protein 5A. Without the lipid droplet due to inhibition of nonstructural protein 5A, full viral RNA replication is unable to occur. Envelope glycoproteins are acquired through budding into the endoplasmic reticulum lumen. The immature, non-infective virions are released via the cellular golgi apparatus.

Pilocarpine, commonly known as Isopto Carpine, is a muscarinic cholinergic agonist that regularly comes as an eye drop for intraocular pressure, Glaucoma, or to induce miosis. Pilocarpine is an agonist of muscarinic acetylcholine receptors subtype M1, M2, and M3. It is also a partial agonist for M4 muscarinic acetylcholine receptor. However approximately 60% to 75% of muscarinic acetylcholine receptors in the ciliary and iris sphincter muscles of the eye are the M3 subtype. By activating these receptors, the iris and ciliary muscles contract causing miosis, spasm of accommodation, and may cause a rise in intraocular pressure followed by a persistent fall. Muscarinic acetylcholine receptors M3 are coupled to the Gq signaling cascade. The activation of this leads to the acitvation of phospholipase C, which converts Phosphatidylinositol (3,4,5)-trisphosphate to inositol (3,4,5)-trisphosphate (IP3) and diacylglycerol (DAG). IP3 activates IP3 receptors on the sarcoplasmic reticulum leading to the release of stored calcium into the cytosol. DAG activates protein kinase C (PKC). One of the downstream effects of PKC include activation of calcium channels on the membrane, leading to influx of calcium ions into the cytosol. Both IP3 and DAG increase cytosolic levels of calcium which then binds to calmodulin to create a calcium-calmodulin complex. This complex activates myosin kinase. Muscle contraction and relaxation are controlled by the enzymes myosin kinase and myosin phosphatase. Myosin kinase phosphorylates myosin light chain, leading to interaction between actin and myosin, producing muscle contraction. Myosin phosphorylase dephosphorylates the phosphorylated myosin light chain, preventing interaction with actin, producing muscle relaxation. The calcium-calmodulin activates myosin kinase, leading to increased phosphorylation of myosin light chain and more muscle contraction. The activation of muscarinic acetylcholine receptor M3 continues to activate myosin kinase which leads to continued contractions of the ciliary or iris sphincter muscles. Pilocarpine is also an agonist of the muscarinic acetylcholine receptors M1, M2, and M4, however, they are much less present within the ciliary and iris sphincter muscles. M1 is also Gq coupled so has the same mechanism. M2 and M4 inhibit Adenylate cyclase, but that is not important in the contraction of the eye muscles. Pilocarpine is also only a partial agonist of M4.