Adrenergic Receptors

α2-adrenergic Receptors

α₂-adrenergic receptors (α₂AR) have structures that are typical for class A GPCRs, with seven transmembrane spanning domains, three extracellular loops and three intracellular loops. The amino-terminus is extracellular and the carboxy-terminal tail is intracellular. Of note, the third intracellular loop is quite large compared to its cytoplasmic tail. There are three human subtypes. Most GPCRs have a fourth intracellular loop formed by the proximal part of the tail anchored to the plasma membrane by palmitoylated cysteines. Of note, the α_2CAR does not have these cysteines. Also most GPCRs have an N-linked glycosylation sites in the amino-terminus, but the α_2BAR does not.

We have identified and characterized the structural basis of α₂AR subtype signaling, as well as polymorphisms which we have found in the genes of each subtype.

Some publications from the lab relevant to these topics are:

• Bristow MR, Murphy GA, Krause-Steinrauf H, Anderson JL, Carlquist JF, Thaneemit-Chen S, Krishnan V, Abraham WT, Lowes BD, Port JD, Davis GW, Lazzeroni LC, Robertson AD, Lavori PW, and Liggett SB. An alpha2C-adrenergic receptor polymorphism alters the norepinephrine-lowering effects and therapeutic response of the beta-blocker bucindolol in chronic heart failure. Circ Heart Fail 3: 21-28, 2010.

• Kardia SL, Kelly RJ, Keddache MA, Aronow BJ, Grabowski GA, Hahn HS, Case KL, Wagoner LE, Dorn GW, 2nd, and Liggett SB. Multiple interactions between the alpha 2C- and beta1-adrenergic receptors influence heart failure survival. BMC Med Genet 9: 93, 2008.

• Small KM, Schwarb MR, Glinka C, Theiss CT, Brown KM, Seman CA, Liggett SB. α_2A- and α_2C adrenergic receptors form homo- and heterodimers: the heterodimeric state impairs agonist-promoted GRK phosphorylation and b-arrestin recruitment. Biochemistry 45:4760-4767, 2006.

• Small KM, Brown KM, Seman CA, Theiss CT, Liggett SB. Complex haplotypes derived from non-coding polymorphisms of the intronless α_2A-adrenergic gene diversify receptor expression. Proc Nat Acad Sci 103:5472-5477, 2006.

• Small KM, Mialet-Perez J, Seman CA, Theiss CT, Brown KM, Liggett SB. Polymorphisms of the cardiac presynaptic α_2Cadrenergic receptors: diverse intragenic variability with haplotype-specific functional effects. Proc Nat Acad Sci 101:13020-13025, 2004.

• Small KM, Wagoner LE, Levin AM, Kardia SLR, Liggett SB. Synergistic polymorphisms of α₁- and α_2C-adrenergic receptors and the risk of congestive heart failure. New England Journal of Medicine 347:1135-1142, 2002.

• Liang M, Eason MG, Theiss CT, Liggett SB. Phosphorylation of Ser³⁶⁰ in the third intracellular loop of the α_2A-adrenoceptor during protein kinase C-mediated desensitization. Eur J Pharmacol 437(1-2):41-46, 2002.

β-adrenergic Receptors

β-adrenergic receptors (βAR) are expressed on many tissues. Our interest has been on the structural basis of their signaling, the physiological importance in heart failure (β1AR and β2AR subtypes) and asthma (β2AR), and discovery and characterization of receptor polymorphisms.

Some publications from the lab relative to these studies include:

• Wang WC, Juan AH, Panebra A, and Liggett SB. MicroRNA let-7 establishes expression of beta2-adrenergic receptors and dynamically down-regulates agonist-promoted down-regulation. Proc Natl Acad Sci U S A 108: 6246-6251, 2011.

• Wang WC, Mihlbachler KA, Brunnett AC, and Liggett SB. Targeted transgenesis reveals discrete attenuator functions of GRK and PKA in airway beta2-adrenergic receptor physiologic signaling. Proc Natl Acad Sci U S A 106: 15007-15012, 2009.

• Swift SM, Gaume BR, Small KM, Aronow BJ, and Liggett SB. Differential coupling of Arg- and Gly389 polymorphic forms of the beta1-adrenergic receptor leads to pathogenic cardiac gene regulatory programs. Physiol Genomics 35: 123-131, 2008.

• Liggett SB, Cresci S, Kelly RJ, Syed FM, Matkovich SJ, Hahn HS, Diwan A, Martini JS, Sparks L, Parekh RR, Spertus JA, Koch WJ, Kardia SL, and Dorn GW, 2nd. A GRK5 polymorphism that inhibits beta-adrenergic receptor signaling is protective in heart failure. Nature Medicine 14: 510-517, 2008.

• McGraw DW, Elwing JM, Fogel KM, Wang WCH, Glinka CB, Mihlbachler KA, Rothenberg ME, Liggett SB. Crosstalk between Gi and Gq/Gs pathways in airway smooth muscle regulates bronchial contractility and relaxation. J Clin Invest 117:1391-1398, 2007.

• Swift SM, Schwarb MR, Mihlbachler KA, Liggett SB. Pleiotropic β-agonist-promoted receptor conformations and signals independent of intrinsic activity. Am J Respir Cell Mol Biol 36:236-243, 2007.

• McGraw DW, Fogel KM, Kong S, Kranias EG, Aronow BJ, Liggett SB. Transcriptional response to persistent β₂-adrenergic receptor signaling reveals regulation of phospholamban which alters airway contractility. Physiol Genomics 27:171-177, 2006.

• Liggett SB, Mialet-Perez J, Thaneemit-Chen S, et al. A polymorphism within a conserved b1-adrenergic receptor motif alters cardiac function and β-blocker response in human heart failure. Proc Nat Acad Sci 103(30):11288-11293, 2006.

• McGraw DW, Mihlbachler KA, Schwarb MR, Rahman FF, Small KM, Almoosa KF, Liggett SB. Airway smooth muscle prostaglandin-EP1 receptors directly modulate β₂-adrenergic receptors within a unique heterodimeric complex. J Clin Invest 116(5):1400-1409, 2006.

• Mialet-Perez J, Green SA, Miller WE, Liggett SB. A primate-dominant third glycosylation site of the β₂-adrenergic receptor routes receptors to degradation during agonist regulation. J Biol Chem 279:38603-38607, 2004.

• Perez JM, Rathz DA, Petrashevskaya NN, Hahn HS, Wagoner LE, Schwartz A, Dorn GW II, Liggett SB. β₁-adrenergic receptor polymorphisms confer differential function and predisposition to heart failure. Nature Medicine 9:1300-1305, 2003.