- American Medical Association Report on Medical Marijuana AMA_Report
- Rhode Island and Washington Governors petition to rechedule Marijuana Chafee_Christie
- American College of Physicians “Supporting Research into the Therapeutic Role of Marijuana medmarijuana
Favorable reports on the use of medicinal cannabis and support to move this off of Schedule I to Schedule II so it can be more thoroughly tested.
- The Gene Controlling Marijuana Psychoactivity.
Sirikantaramas, S., Morimoto, S., Shoyama, Y., Ishikawa, Y., Wada, Y., Shoyama, Y. & Taura, F. (2004). J. Biol. Chem.279, 39767–39774.
An excellent paper demonstrating THC Synthase and the mutations in this gene which can effect and predict THC production from seedling stage. The gene is especially sensitive to mutations in the Flavin binding sites for FAD.
- The Inheritence of Chemical Phenotypes in Cannabis sativa L.
de Meijer EP, Bagatta M, Carboni A, Crucitti P, Moliterni VM, Ranalli P, Mandolino G. (2003) Genetics 163, 335-346
This paper makes back crosses of CBD and THC pure strains and then recrosses them to test if the THC synthase and CBD synthase genes are in linkage (genetically close or in the same neighborhood on the same chromosome). Based on these crosses it appears it is difficult to get strains which are high in both THC and CBD content and it implies a monogenic gene or two genes in very close proximity. The model doesn’t test for copy number variation or others forms of genetic variation which may produce this observation.
- DNA polymorphisms in the tetrahydrocannabinolic acid (THCA) synthase gene in “drug-type” and “fiber-type” Cannabis sativa L.
Mareshige Kojoma, Hikaru Seki, Shigeo Yoshida, Toshiya Muranaka Forensic science international 2 June 2006 (volume 159 issue 2 Pages 132-140 DOI: 10.1016/j.forsciint.2005.07.005)
A review of SNPs (Single Nucleotide Polymorphisms) which exist in fiber strains vs “drug” strains. Several mutations exist. Most are outside of the Flavin binding site but presumably impact THC synthase activity. Simple phylogenetic classification of this gene can predict THC or no THC status of the plant.
- Novel cannabinoid receptors
Up until the 1990s, the receptors for THC, CBD and all cannabinoids were a mystery. CB1 and shortly thereafter CB2, were discovered as human cannabinoid receptors or Endocannabinoid receptors for Anandamide. This led to the hunt for the other analogs of THC such as 2-AG and its metabolic pathyway partners. As confusing results began to materialize on the role of CBD and THC, researches became more convinced there were other Endocannabinoid receptors in the human body that must explain the pathway characteristics more precisely. After the human genome project completed there were 100s of novel or “orphan” G-Protein Coupled Receptors (GPCRs) discovered in the human genome. GPCRs make up the majority (50%) of the drug industries targets (seratonin and dopamine receptors, etc) but these orphan GPCRs researchers assumed were extinct olfactory receptors from our primate inheritance. Now quite compelling work is showing that 3 of these orphan GPCRs (GPR55, GPR119, GPR18) may be the missing pieces of the endocannabinoid puzzle. The higher affinity of CBD for these receptors and the unique CB1 expression in other tissues, help to explain the variety of therapeutic effect people see with different Cannabis strains.
Not everyone’s GPCRs are identical. Mutations in genes coding for GPCRs are known to account for altered drug response (1) yet sequencing has never been more affordable to measure this effect. Sequencing of these endocannabinoid receptors and other enzymes in these pathways has already helped to explain differences in Body Mass Index (BMI) and will likely help explain other patient responses (See Harismendy et al. below).
- Population sequencing of two endocannabinoid metabolic genes identifies rare and common regulatory variants associated with extreme obesity and metabolite level
Harismendy, Olivier, Bansal, Vikas, Bhatia, Gaurav, Nakano, Masakazu, Scott, Michael, Wang, Xiaoyun, et al.(2010).Genome Biology, 11(11), R118. doi: http://dx.doi.org/10.1186/gb-2010-11-11-r118.
This team sequenced 2 human genes in the endocannabinoid pathway. Both FAAH and MGLL were sequenced in a cohort of individuals on the tails (very high and very low) of the population distribution for Body Mass Index or BMI. This paper demonstrates that human variation in the genes in the endocannabinoid pathyway can have a significant physiological influence. Presumably, similar variations will have an impact on the dosage of THC or CBD required for a desired effect.
- Palmitoylation of cysteine 415 of helix 8: effect on membrane localisation and signalling of the CB(1) cannabinoid receptor.
Source
Department of Biomedical Sciences, University of Teramo, Teramo, Italy. European Center for Brain Research (CERC)/Santa Lucia Foundation I.R.C.C.S., Rome, Italy. Neuroscience/Drug Abuse Research Program, Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC, USA. Department of Experimental Medicine and Biochemical Sciences, University of Rome “Tor Vergata”, Rome, Italy. Department of Biomedical Sciences, University of Chieti-Pescara “G. d’Annunzio”, Chieti, Italy. Department of Neurosciences, University of Rome “Tor Vergata”, Rome, Italy. Research Group of biomedical Informatics (GRIB-IMIM), University of Pompeu Fabra, Barcelona Biomedical Research Park (PRBB), Barcelona, Spain. Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Winston-Salem, NC, USA.
Abstract
Background and purpose: The CB(1) cannabinoid receptor is regulated by its association with membrane microdomains like the lipid rafts. Here we investigated the role of CB(1) palmitoylation by analyzing the functional consequences of site-specific mutation of cysteine 415, the likely palmitoylated residue at the end of helix 8, in terms of membrane association, raft targeting and signalling of the receptor. Experimental approach: The palmitoylation state of the CB(1) receptor was assessed in rat forebrain by depalmitoylation/repalmitoylation experiments. Cysteine 415 was replaced with alanine by site directed mutagenesis. Green fluorescence protein chimeras of both wild-type and mutant receptors were transiently expressed and functionally characterised in SH-SY5Y cells and HEK-293 cells by means of confocal microscopy, cytofluorimetry and competitive binding assays. Confocal FRAP was used to assess receptor membrane dynamics, whereas [(35) S]GTPγS, cAMP and co-immunoprecipitation assays were employed to assess signalling activity. Key results: Endogenous CB(1) receptors were palmitoylated in rat brain. Mutation of cysteine 415 in transfected cells prevented the palmitoylation of the receptor and significantly reduced it recruitment at both plasma membrane and lipid rafts; it also increased protein diffusional mobility. The same mutation markedly reduced the functional coupling of CB(1) receptor with G proteins and adenylyl cyclase, whereas depalmitoylation abrogated receptor association with a specific subset of G proteins. Conclusions and implications: We found that CB(1) receptor is post-translationally modified by palmitoylation and that mutation of cysteine 415 gives rise to a form of receptor that is functionally impaired in terms of membrane targeting and signalling.
© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.
- PMID: 21895628
- Cannabinoids for Cancer Treatment:Progress and Promise
S Sarfaraz, VM Adhami, DN Syed, F Afaq… – Cancer research, 2008 – AACR
1) Alan S. Kopin, Edward W. McBride, Ci Chen, Roger M. Freidinger, Duan Chen, Chun-Mei Zhao, and Martin Beinborn: Identification of a series of CCK-2 receptor nonpeptide agonists: Sensitivity to stereochemistry and a receptor point mutation. PNAS 2003 100 (9) 5525-5530; published ahead of print April 15, 2003,doi:10.1073/pnas.0831223100