Beta-2 Adrenergic Receptor: Difference between revisions

<StructureSection load='2rh1' size='490' side='right' caption='Solved Structures of a Beta 2-Adrenergic Receptor, ([[2rh1]])' scene='Beta-2_Adrenergic_Receptor/Opening/1' >

[[Image:B2ar Image3.png|200px|left]]&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; [[Beta-2 Adrenergic Receptor]]'''s''' (B2ARs) are a type of G Protein-Coupled Receptor (GPCR). GPCRs are the largest family of integral membrane proteins in the human body with over 1000 unique Isoforms. B2AR is activated by hormone ligands like adrenaline (epinephrine) and noradrenaline and plays a critical role in cardiovascular and pulmonary physiology. Binding of adrenaline by B2AR causes a sympathetic nervous system response like the well-known “flight or flight response”, resulting in an increased heart rate, pupil dilation, rapid energy mobilization and diversion of blood to skeletal muscle. More precisely, upon binding a ligand, B2AR activates [[Adenylyl cyclase]] through interaction with B2ARs C-terminus. Adenylyl cyclase subsequently converts ATP into cAMP, which functions as a downstream signaling molecule activating effectors like cAMP-dependent protein kinases, resulting in various bodily responses.<ref name="Witter"/>  

====Strucutre of B2ARs====

&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, binds to the receptor binding pocket 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 Trp 286 to assume an inactive rotameric state, effectively inhibiting B2AR activity.<ref>PMID: 17962520</ref> A conserved DRY motif (residues 129-131) 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 does not interact with Glu 268, 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>

&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Although activation of B2AR upon ligand binding is not fully understood, a recently solved structure of Beta 1 Adrenergic Receptors offers clues. Agonists of B1ARs disrupt the interaction between Val 172 and Ser 215, eliminating a key interaction between helices four and five. Since mutation to Val 172 is known to reduce basal activity, it is likely that the agonists interference of Val 172 has a similar affect.<ref>PMID: 21228877</ref> The class of [[Pharmaceutical Drugs|pharmaceutical drugs]] known as the “beta blockers” are antagonists of B2AR. They diminish the effects of adrenaline, slowing the heart rhythm and reducing blood pressure. B2AR Agonists serve a completely different purpose. These molecules which mimic native ligands of B2AR cause smooth muscle relaxation, bronchial passage dilation, vasodilation and rapid release of insulin. These compounds are used to treat asthma, and include the well-known Albuterol and Terbutaline.<ref>PMID: 20692524</ref>