Beta-2 Adrenergic Receptor

B2AR and Autism

      During embryo development, Beta adrenergic receptors are involved in fetal growth, tissue differentiation and axonal outgrowth. During fetus development, B2AR transcription is progressively downregulated and undergoes desensitization. These steps are essential homeostatic mechanisms to prevent cells from being overly stimulated and maintaining the correct sympathetic to parasympathetic tone. This sympathetic-parasympathetic tone determines the point at which the sympathetic nervous system (flight or fight) overrides the parasympathetic nervous system (responsible for normal cardiovascular homeostasis). The B2AR downregulation and desensitization steps are first established during prenatal development during the first and second trimester.^[1] Interestingly, overstimulation of B2ARs during critical periods of prenatal development can cause a permanent increase in the sympathetic to parasympathetic tone. Overstimulation of this type is caused by stress in the mother for reasons ranging from infections to hardships like natural disasters. Since children with autism typically have an elevated sympathetic tone and elevated B2AR stimulation during development causes an elevated sympathetic tone, this partly explains why children of mothers who survive natural disasters during pregnancy have a higher incidence of Autism Spectrum Disorders (ASDs).^[1]

Fevers and the Locus Coeruleus

      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.^[2] 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 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 intervention.^[2]

Strucutre of B2ARs

      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 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 and an 8th helix which runs parallel to the cytoplasmic face of the membrane.^[3] Helices 2,5,6 and 7 of B2AR have at conserved places, which are important for activation of G protein effectors. The on all GPCRs dictate the ligand specificity of GPCRs. The partial inverse agonist, Carazolol, 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 , effectively inhibiting B2AR activity.^[4] A (residues 130-132) is present in all GPCRs.^[5] 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 , which helps explain why B2AR has basal activity. Interestingly, Rhodopsin has no basil activity, a feature that is critical for vision.^[6]

Pharmaceutical Implications

      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.^[7] The class of 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.^[8]