Sandbox 420: Difference between revisions

K2 and other newly popularized drugs laced with synthetic cannabinoids, which mimic those found in marijuana, bind similarly to G-coupled receptors found throughout the body and nervous system. CB1, in particular, is comprised of 472, mostly nonpolar amino acids that fold into a secondary structure consisting of ten alpha helices and one beta pleated sheet forming a transmembrane domain. Binding to endogenous and exogenous ligands alike, CB1 acts as an activator in a signal transduction pathway to aid in regulating many major bodily systems.

You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.

Synthetic cannabinoids (SCBs) are chemically derived forms of the naturally-occurring psychotropic cannabinoid, tetrahydrocannabinol (THC), found in marijuana <ref name="k2">DOI 10.3109/03602532.2013.839700</ref> <ref name = "cardio">"The History of Synthetic Drugs (Spice, K2 and Bath Salts)." ''Narconon International''. Web. 17 Nov. 2015. </ref>. Cannabinoids bind and activate cannabinoid receptors, CB1R and CB2R, which are found throughout the body <ref name="k2" />.  CB1 is primarily found in the cerebellum as well as the hippocampus, hypothalamus, cerebral cortex, striatum and brainstem; all vital areas of the central nervous system <ref name="k2" />.  

Although SCBs are chemically similar to THCs, which exhibit relatively mild side effects when used recreationally, the use of K2 has been linked to many serious health conditions. Due to the delocalization of CB1 receptors throughout the body and in crucial parts of the CNS that regulates bodily functions, K2 can affect many systems of the body simultaneously. Cardiovascularly, K2 can cause tachycardia, tachyarrhythmia,  hypertension and, in rare cases, myocardial infarction <ref name="cardio" /> (3,4). Neurologically, K2 can cause extreme paranoia, psychosis, hallucinations, memory and learning disruptions, dependence and even seizures <ref name="k2" />.  

Primary: The cannabinoid receptor (CB1) has a total of 472 amino acids. Of the 472 amino acids, 52.75% are nonpolar, 26.91% are uncharged polar, and 20.34% are polar (12.08% basic and 8.26% acidic).

</td></tr><tr id='Nonpolar Amino Acids Residues'><td class="sblockLbl"><b>[[Nonpolar Amino Acids Residues]]</b></td><td class="sblockDat"><scene name='71/716602/Alanine_residues/2'>Ala </scene>,<scene name='71/716602/Phe/1'>Phe</scene></td></tr>

<tr id='Uncharged Polar Amino Acids'><td class="sblockLbl"><b>[[Uncharged Polar Amino Acids]]</b></td><td class="sblockDat">[[3nms|3nms]], [[3l3o|3l3o]]</td></tr>

<tr id='Polar Amino Acids'><td class="sblockLbl"><b>[[Polar Amino Acids]]</b></td><td class="sblockDat">SAV1942, scn ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=158878 Staphylococcus aureus subsp. aureus Mu50])</td></tr>

Secondary: The secondary structure of CB1 is made up of of ten α-helices and one β-sheet. Of the ten α-helices, eight are roughly identical in size and align parallel to one another to form a typical transmembrane-type domain. The remaining two α-helices are shorter in length, run perpendicular to the other eight, and are located at one end of the receptor. On the opposite end of the receptor, an antiparallel β-sheet is located in the middle of the transmembrane domain formed by the eight parallel helices. While the structure overall has a low composition of polar amino acids, a large portion are located within this β-sheet, hinting at the role it may play in the function of the receptor.  

In neurons, CB1 is presynaptic and modulates neurotransmitter release by retrograde signalling, meaning the message travels from postsynaptic neurons to presynaptic neurons. When the agonist binds to CB1, a conformational change occurs in the receptor, inducing an interaction between CB1 and a heterotrimeric G-protein (1). This heterotrimeric protein is bound to guanosine diphosphate (GDP), but the interaction causes an exchange of GDP to guanosine triphosphate (GTP), which catalyzes the dissociation of the heterotrimeric G-protein and promotes several signalling cascades. This activity inhibits intracellular cyclic AMP (cAMP) production, opening of some voltage gated calcium channels, and activates some potassium channels (1). The inhibition of opening calcium channels and the activation of potassium channels, which both cause hyperpolarization, make it more difficult to excite an action potential in a neuron. There is an increase in the amount of dopamine present in the brain which promotes the brain reward system. This is due to inhibition of dopaminergic neurons that would take up this dopamine. The agonists cause an inhibitory effect on neuronal function (1). In contrast to cannabis, K2 is synthetic and contains multiple SCBs that participate in drug-drug interactions. These interactions promote potency of synergistic effects, but they also contribute negative side effects (10).  

CB1 is one of two receptors in the human body that recognizes five endocannabinoid compounds as well as exogenous cannabinoids like THC and K2. The CB1 receptor is a G-protein coupled receptor (GPCR) located primarily in the nervous system (5). The primary function of the CB1 receptor is to bind endogenous and exogenous ligands to activate signal transduction pathways for the cells in which they are located (5). The function of CB1 receptors thus depends on the location of the receptor as well as the type of ligand binding to the receptor. As a result, CB1 receptors are involved in regulating a variety of physiological functions including regulation of neurotransmitters, pain modulation, memory, motor control, control of appetite, and regulation of anxiety.

The highest concentration of CB1 receptors is found within presynaptic nerve terminals (6). When ligands bind to CB1 receptors in presynaptic nerve terminals, calcium channels are inhibited. The release of calcium is a key component of nerve signal transduction pathway that results in the release of neurotransmitters in the synaptic cleft. As a result, activated CB1 receptors are able to regulate the release of neurotransmitters. CB1 receptors have been shown to inhibit the release of glutamate, acetylcholine, and noradrenaline (5).  

 

Additionally,  activated CB1 receptors suppresses the activity of GABAergic neurons,  which control neurons responsible for the release of dopamine (7). By suppressing GABAergic neurons, dopamine levels in the brain are increased. This action of CB1 receptors is responsible for the pleasure associated the THC use and the potential for abuse of exergonic cannabinoids.   

CB1 receptors are also highly expressed in areas of the nervous system involved with pain modulation, specifically in the dorsal root ganglia (5). This is one of the most well known functions of CB1 receptors and is responsible for the pain reduction effects associated with THC.  

CB1 receptors are also highly concentrated in the hippocampus. The hippocampus is a region of the brain involved with learning and memory (7). The relatively high density of CB1 receptors in the hippocampus is responsible for the memory-altering effects of THC and other cannabinoids (8).  

CB1 receptors are also located in the basal ganglia, a region of the brain responsible for the coordination of movement (5). The binding of endocannabinoids has been shown to play a critical role in fine motor control. Specifically, it has been shown that CB1 receptor binding is decreased in patients with neurodegenerative diseases such as Parkinson’s and Huntington’s disease. In contrast, CB1 receptors have a lesser influence on gross motor control due to the lower concentration of receptors in the cerebellum, which is responsible for coordinating gross motor control (5).