Browsing Pathways

The main psychoactive component in cannabis, △9-tetrahydrocannabinol (THC), acts on CB1 receptors in the brain located on synaptic terminals. THC, whose 3D structure closely resembles that of the endogenous cannabinoid anandamide, acts as a partial agonist on these receptors. Several behavioural effects of cannabis are feelings of euphoria, relaxation, lack of concentration,and altered time perception, while physiological effects range from increased appetite to rapid changes in heart rate. The mechanism of action of THC works through the activation CB1, which inhibits adenylate cyclase and lowers levels of cyclic AMP in the cell. This further inhibits protein kinase A complex, which affects regulating synaptic membrane exocytosis protein through an as yet unknown mechanism. This regulating protein is responsible for the release of GABA or ɣ-aminobutyric acid by exocytosis from the inhibitory terminal of the neuron. GABA is normally released to inhibit and regulate the release of dopamine in the brain. The binding of THC limits the exocytosis of GABA, and so dopamine is able to travel along synapses and bind to receptors. This promotes the well-known euphoric effects of cannabis. The activated CB1 receptor also interacts with its normal physiological targets, activating both MAPK and potassium channels and inhibiting calcium channels. These interactions and their physiological downstream effects are responsible for the numerous side effects associated with cannabis such as lack of concentration and impaired learning. The sustained effects of THC can be explained by the ability of CB1 receptors to influence long term plasticity in the brain.

Ascorbate (Vitamin C) is a very important molecule in the brain. Ascorbate is transported into brain through Sodium-dependent Vitamin C Transporter-2 (SVCT2), and will be reduced to dehydroascorbic acid, which is the oxidized form of ascorbate. Dehydroascorbic acid is transported into extracellular place and enter astrocyte space via Solute carrier family 2, facilitated glucose transporter members (GLUT family). Once dehydroascorbic acid in astrocyte cells, it is rapidly reduced to ascorbate to do further reactions that are associated with other pathways. Ascorbate is proposed as a neuromodulator of glutamatergic, dopaminergic, cholinergic and GABAergic transmission and related behaviors; it also has a number of other important functions, participating as a co-factor in several enzyme reactions including catecholamine synthesis, collagen production and regulation of HIF-1α.

Interleukin-10 (IL-10) is an anti-inflammatory cytokine with important immunoregulatory functions. It is primarily secreted by antigen-presenting cells such as activated T-cells, monocytes, B-cells and macrophages. In biologically functional form, it exists as a homodimer that binds to tetrameric heterodimer IL-10 receptor and induces downstream signaling. IL-10 is associated with survival, proliferation and anti-apoptotic activities of various cancers such as Burkitt lymphoma, non-Hodgkins lymphoma and non-small scell lung cancer. In addition, it plays a central role in survival and persistence of intracellular pathogens such as Leishmania donovani, Mycobacterium tuberculosis and Trypanosoma cruzi inside the host.

Akt (v-Akt Murine Thymoma Viral Oncogene) is a serine kinase that is involved in mediating various biological responses, such as inhibition of apoptosis and stimulation of cell proliferation. Activation of Akt can begin with several events, mainly the binding of a ligand to a receptor in the cell membrane. Most common ligands activating Akt include growth factors, cytokines, mitogens and hormones. The actions of Akt in the cell are numerous and diverse, but all result in anti-apoptosis, or pro-cell proliferation effects. These physiological roles of Akt include involvement in metabolism, protein synthesis, apoptosis pathways, transcription factor regulation and the cell cycle. The downstream targets of Akt include BAD (BCL2 Antagonist of Cell Death), Caspase-9, FKHRL (Forkhead Transcriptional Factor), IKK (I-KappaB Kinase), and mTOR (Mammalian Target of Rapamycin). Akt inhibits apoptosis by phosphorylating the BAD component of the BAD/BclXL (Bcl2 Related Protein Long Isoform) complex. Phosphorylated BAD binds to 14-3-3, causing dissociation of the BAD/BclXL complex and allowing cell survival. Akt activates IKK, which ultimately leads to NF-KappaB activation and cell survival. Other direct targets of Akt are members of the FKHRL. In the presence of survival factors, Akt1 phosphorylates FKHRL1, leading to the association of FKHRL1 with 14-3-3 proteins and its retention in the cytoplasm. Survival factor withdrawal leads to FKHRL1 dephosphorylation, nuclear translocation and target gene activation. Within the nucleus, FKHRL1 most likely triggers apoptosis by inducing the expression of genes that are critical for cell death, such as the Fas ligand (TNF superfamily, member 6) gene. Another notable substrate of Akt is the protease Caspase-9. Phosphorylation of Caspase-9 decreases apoptosis by directly inhibiting the protease activity. Akt may also be involved in activation of the nutrient-dependent Thr/Ser kinase, mTOR.

The V2 receptor is expressed in the kidney tubule, predominantly in the distal convoluted tubule and collecting ducts, where its primary property is to respond to the pituitary hormone arginine vasopressin (AVP) by stimulating mechanisms that concentrate the urine and maintain water homeostasis in the organism. When the function of this gene is lost, the disease Nephrogenic Diabetes Insipidus (NDI) results. The V2 receptor is also expressed outside the kidney although its tissue localization is uncertain. When these ‘extrarenal receptors’ are stimulated by infusion of a V2 selective agonist (dDAVP), a variety of clotting factors are released into the bloodstream. The physiologic importance of this property is not known. The V2 receptor activates G(s) proteins which lead to the activation of adenylyl cyclase which produces the secondary messenger cAMP. cAMP activates PKA (protein kinase A) which phosphorylates downstream effectors that lead to a specific cellular response.

Guanosine nucleotide-binding proteins (G proteins) are a class of proteins involved in transmitting extracellular stimuli to the inside of a cell. G proteins are activated by G protein-coupled receptors (GPCRs) on the membrane, which activate intracellular G proteins in respond to extracellular signaling factors such as hormones and neurotrasmitters. Activated GPCRs act as guanine nucleotide exchange factors, exchanging the GDP on the alpha subunit of inactive G proteins for GTP, thus turning the G proteins "on". G proteins may be mononmeric of trimeric. Monomeric G proteins consist of only the alpha subunit. Trimeric G proteins also have beta and gamma subunits, which dissocate from the alpha subunit together after activation. Once activated, both the alpha and beta/gamma subunits can then activate different signaling cascades. The alpha subunit eventually hydrolyzes the attached GTP to GDP using its inherent enzymatic activity, allowing it to re-associate and start a new cycle. Regulatory proteins may accelerate this hydrolysis to speed up signal termination. G proteins regulate numerous metabolic enzymes, ion channels, transporters, and other parts of the cell machinery.

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The long intergenic non coding RNA, LINK-A interacts with PIP3 to recruit AKT to the celll membrane thus facilitating its phosphorylation by PDK1 and MTOR. This leads to hyper-activation of AKT.