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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 α2CAR does not have these cysteines. Also most GPCRs have an N-linked glycosylation sites in the amino-terminus, but the α2BAR 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:

  • Small KM, Schwarb MR, Glinka C, Theiss CT, Brown KM, Seman CA, Liggett SB. α2A- and α2C 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 α2A-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 α2Cadrenergic 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 α2C-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 α2A-adrenoceptor during protein kinase C-mediated desensitization. Eur J Pharmacol 437(1-2):41-46, 2002.

  • Liang M, Freedman NJ, Theiss CT, Liggett SB. Serine 232 of the α2A-adrenergic receptor is a protein kinase C-sensitive effector coupling switch. Biochemistry 40:15031-15037, 2001.

  • Small KM, Brown KM, Forbes SL, Liggett SB. Polymorphic deletion of three intracellular acidic residues of the α2B-adrenergic receptor decreases G protein-coupled receptor kinase-mediated phosphorylation and desensitization. J Biol Chem 276:4917-4922, 2001.

  • Small KM, Forbes SL, Brown K, Liggett SB. An Asn to Lys polymorphism in the third intracellular loop of the human α2A-adrenergic receptor enhances agonist-promoted Gi coupling. J Biol Chem 275:38518-38523, 2000.

  • Small KM, Forbes SL, Rahman FF, Bridges KM, Liggett SB. A four amino acid deletion polymorphism in the third intracellular loop of the human α2C-adrenergic receptor confers impaired coupling to multiple effectors. J Biol Chem 275:23059-23064, 2000.

  • Jewell-Motz EA, Small KM, Liggett SB. α2A/α2C-adrenergic receptor third loop chimera show that agonist interaction with receptor-subtype backbone establishes GRK phosphorylation. J Biol Chem 275:28989-28993, 2000.

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:

  • 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.

  • Akhter SA, D'Souza KM, Petrashevskaya NN, Mialet-Perez J, Liggett SB. Myocardial β1-adrenergic receptor polymorphisms affect functional recovery following ischemic injury. Am J Physiol 290:H1427-H1432, 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.

  • McGraw DW, Almoosa KF, Paul RJ, Kobilka BK, Liggett SB. Antithetic regulation by β-adrenergic receptors of Gq-receptor signaling via phospholipase-C underlies the airway b-agonist paradox. J Clin Invest 112:619-626, 2003.

  • Rathz DA, Gregory KN, Fang Y, Brown KM, Liggett SB. Hierarchy of polymorphic variation and desensitization permutations relative to β1- and β2-adrenergic receptor signaling. J Biol Chem 278:10784-10789, 2003.

  • Small KM, Wagoner LE, Levin AM, Kardia SLR, Liggett SB. Synergistic polymorphisms of β1- and α2C-adrenergic receptors and the risk of congestive heart failure. New England Journal of Medicine 347:1135-1142, 2002.

  • Small KM, Brown KM, Forbes SL, Liggett SB. Modification of the β2-adrenergic receptor to engineer a receptor-effector complex for gene therapy. J Biol Chem 276(34):31596-31601, 2001.

  • McGraw DW, Fukuda N, James PF, Forbes SL, Woo AL, Lingrel JB, Witte DP, Matthay MA, Liggett SB. Targeted transgenic expression of β2-adrenergic receptors to type II cells increases alveolar fluid clearance. Am J Physiol Lung Cell Mol Physiol 281:L895-L903, 2001.

  • Drysdale CM, McGraw DW, Stack CB, Stephens JC, Judson RS, Nandabalan K, Arnold K, Ruano G, Liggett SB. Complex promoter and coding region β2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. Proc Nat Acad Sci 97:10483-10488, 2000.

  • McGraw DW, Forbes SL, Mak JCW, Witte DP, Carrigan PE, Leikauf GD, Liggett SB. Transgenic overexpression of β2-adrenergic receptors in airway epithelial cells decreases bronchoconstriction. Am J Physiol Lung Cell Mol Physiol 279:L379-L389, 2000.

  • Liggett SB, Tepe NM, Lorenz JN, Canning AM, Jantz TD, Mitarai S, Yatani A, Dorn GW II, Early and delayed consequences of β2 adrenergic receptor overexpression in mouse hearts: critical role for expression level. Circulation 101:1707-1714, 2000.

  • Small KM, Forbes SL, Rahman FF, Liggett SB. Fusion of β2-adrenergic receptor to Gas in mammalian cells: Identification of a specific signal transduction species not characteristic of constitutive activation or precoupling. Biochemistry 39(10):2815-2821, 2000.