Beta-2 adrenergic receptor: Difference between revisions

=='''Cannabinoid Receptor 1 (CB1)'''==

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). The location of the amino acid residues can be viewed by by selecting the name of each amino acid in the table below.  

The secondary structure of CB1 is made up of of ten <scene name='71/716602/Alpha_helices/1'>α-helices</scene> and one <scene name='71/716602/Beta_sheet/1'>β-sheet</scene>. 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.  

A homology model for the tertiary structure of CB1 is shown in the upper righthand corner of the page with the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref><ref>PMID:21638687</ref>.

In neurons, CB1 is presynaptic and modulates neurotransmitter release by retrograde signalling, meaning the message travels from postsynaptic neurons to presynaptic neurons. The portion of the receptor with eight alpha helices spans the membrane, giving an active site on the extracellular portion of the receptor. This active site is filled with <scene name='71/716602/Polar_side_chains/1'>polar</scene> side chains, allowing for hydrogen bonding of the <scene name='71/716602/Ligand_bound/1'>ligand</scene> which is nonpolar. When the agonist binds to CB1, a conformational change occurs in the receptor. The beta sheet and other two alpha helices are intracellular, and after the conformational change this portion produces a binding site for a heterotrimeric G-protein <ref name="k2" />. 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 <ref name="k2" />. 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 <ref name="k2" />. 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 <ref>PMID: 24084047</ref>.  

The highest concentration of CB1 receptors is found within presynaptic nerve terminals <ref>PMID: 16723537</ref>. 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 <ref name = "review"/>. Additionally,  activated CB1 receptors suppresses the activity of GABAergic neurons,  which control neurons responsible for the release of dopamine <ref name ="g">DOI 10.1073/pnas.1016442108</ref>. 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 responsible for mediating the anti-anxiety effects of cannabinoids, like THC. In low doses, cannabinoids reduce anxiety; however, high doses of cannabinoids act to increase anxiety <ref name="toxic" />. This is one reason why synthetic cannabinoids like K2, an extremely potent synthetic cannabinoid, produces the harmful side effect of extreme anxiety.