Beta-2 Adrenergic Receptor: Difference between revisions

&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;As an aside, stress during prenatal development has also been proven to impact locus coeruelus (LC) development. Nearly all adrenaline in the brain is produced and transported by neurons in the Locus Coeruleous, a small area of the brain. The locus coeruleus-Noradrenergic System (LC-NA) plays a crucial role in virtually all aspects of behavioral adaptations and performance of cognitive regions of the brain commonly affected in ASDs.<ref name="Purpura">PMID: 19059284</ref> Critical enzymes for proper LC can be downregulated by aberrant epigenetic modifications caused by prenatal stress. One well known example of this is hypomethylation of the Crh gene. When methylated, the Crh promotor is bound by the transcriptional repressor, [[MeCP2]]. Aberrant epigenetic modifications caused by prenatal stress can cause Crh promoters to be under methylated, preventing MeCp2 binding and subsequently causing overexpression of the Crh gene. Overexpression of the Crh gene is a trademark of Rett Syndrome, a well known [[Neurodevelopmental Disorders|neurodevelopmental disorder]] Interestingly, when some autism patients have a fever, the LC-NA system dysfunction abates resulting in reduced autistic behaviors. This implies that the underlying neural networks mediating the LC-NA system are still functional, and offers hope for partial reversal of ASDs through [[Pharmaceutical Drugs|pharmaceutical intervention]].<ref name="Purpura"/>  

&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;As a family, GPCRs are renowned for their structure solution difficulty. In this model, Beta2-Adrenergic  Receptor (B2AR) – T4 Lysozyme fusion was developed to allow for structure solution. Fortunately, the <scene name='Beta-2_Adrenergic_Receptor/Opening_lyso/1'>lysozyme portion</scene> of the structure does not appear to impact the structure of the B2AR. The structure of B2AR is very similar to the GPCR [[Rhodopsin]], which is a photoreceptor in the retina which allows the perception of light. B2AR is a transmembrane protein with <scene name='Beta-2_Adrenergic_Receptor/Helices/1'>7 transmembrane helices</scene> and an 8th helix which runs parallel to the cytoplasmic face of the membrane.<ref name="Rasmussen">PMID: 17952055</ref>  Helices 2,5,6 and 7 of B2AR have <scene name='Beta-2_Adrenergic_Receptor/Kinks/1'>kinks caused by prolines</scene> at conserved places, which are important for activation of G protein effectors. The <scene name='Beta-2_Adrenergic_Receptor/Extracellular_residues/1'>extracellular regions</scene> on all GPCRs dictate the ligand specificity of GPCRs. The partial inverse agonist, Carazolol, <scene name='Beta-2_Adrenergic_Receptor/Cara_binding/1'>binds to the receptor binding pocket</scene> of B2AR, reducing the basal activity of the receptor. This interaction involves residues Tyr 199, Ser 203, Ser 207, Phe 193, Ser 204, Ser 293, Phe 290, Tyr 308, Phe 289, Asn 312, Tyr 316, Trp 286, Trp 109 and Asp 113. Carazolol occupies a similar position as the rhodopsin inverse agonist, retinal. Carazolol does not act with the so called “toggle switch” on helix 6, but does interact with Phe 290, causing <scene name='Beta-2_Adrenergic_Receptor/Cara_binding_w/1'>Trp 286 to assume an inactive rotameric state</scene>, effectively inhibiting B2AR activity.<ref>PMID: 17962520</ref> A <scene name='Beta-2_Adrenergic_Receptor/Dry/1'>conserved DRY motif</scene> (residues 130-132) is present in all GPCRs.<ref>PMID: 18547522</ref> In rhodopsin, the Arginine in this motif forms a salt bridge with a glutamate, an interaction that maintains rhodopsin in its inactive state until it is exposed to light. In B2AR, Arg 131 <scene name='Beta-2_Adrenergic_Receptor/Dry_no_salt/1'>does not interact with Glu 268</scene>, which helps explain why B2AR has basal activity. Interestingly, Rhodopsin has no basil activity, a feature that is critical for vision.<ref>PMID: 18818650</ref>