The dopamine D1 receptor is expressed and facilitates relaxation in airway smooth muscle

Respiratory Research

Charles W Emala¹  Eiji Masaki³  Frank D’Ovidio²  Fumiko Mizuta³  Dingbang Xu¹  Yi Zhang¹  Kentaro Mizuta³ 

[1] Departments of Anesthesiology, College of Physicians and Surgeons of Columbia University, 630W 168th St, P&S Box 46, New York, NY 10032, USA;Departments of Surgery, College of Physicians and Surgeons of Columbia University, 622W 168th St, PH 14, Room 104, New York, NY 10032, USA;Department of Dento-oral Anesthesiology, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba, Sendai, Miyagi 9808575, Japan

关键词: Epac;    PKA;    Cyclic AMP;    G_s-coupled receptor;    Immunoblot;    RT-PCR;    Dopamine;   

Others  :  792852
DOI  :  10.1186/1465-9921-14-89

 received in 2013-03-14, accepted in 2013-08-29,  发布年份 2013

【 摘 要 】

Background

Dopamine signaling is mediated by G_s protein-coupled “D₁-like” receptors (D₁ and D₅) and G_i-coupled “D₂-like” receptors (D_2-4). In asthmatic patients, inhaled dopamine induces bronchodilation. Although the G_i-coupled dopamine D₂ receptor is expressed and sensitizes adenylyl cyclase activity in airway smooth muscle (ASM) cells, the G_s-coupled dopamine D₁-like receptor subtypes have never been identified on these cells. Activation of G_s-coupled receptors stimulates cyclic AMP (cAMP) production through the stimulation of adenylyl cyclase, which promotes ASM relaxation. We questioned whether the dopamine D₁-like receptor is expressed on ASM, and modulates its function through G_s-coupling.

Methods

The mRNA and protein expression of dopamine D₁-like receptor subtypes in both native human and guinea pig ASM tissue and cultured human ASM (HASM) cells was measured. To characterize the stimulation of cAMP through the dopamine D₁ receptor, HASM cells were treated with dopamine or the dopamine D₁-like receptor agonists (A68930 or SKF38393) before cAMP measurements. To evaluate whether the activation of dopamine D₁ receptor induces ASM relaxation, guinea pig tracheal rings suspended under isometric tension in organ baths were treated with cumulatively increasing concentrations of dopamine or A68930, following an acetylcholine-induced contraction with or without the cAMP-dependent protein kinase (PKA) inhibitor Rp-cAMPS, the large-conductance calcium-activated potassium (BK_Ca) channel blocker iberiotoxin, or the exchange proteins directly activated by cAMP (Epac) antagonist NSC45576.

Results

Messenger RNA encoding the dopamine D₁ and D₅ receptors were detected in native human ASM tissue and cultured HASM cells. Immunoblots confirmed the protein expression of the dopamine D₁ receptor in both native human and guinea pig ASM tissue and cultured HASM cells. The dopamine D₁ receptor was also immunohistochemically localized to both human and guinea pig ASM. The dopamine D₁-like receptor agonists stimulated cAMP production in HASM cells, which was reversed by the selective dopamine D₁-like receptor antagonists SCH23390 or SCH39166. A68930 relaxed acetylcholine-contracted guinea pig tracheal rings, which was attenuated by Rp-cAMPS but not by iberiotoxin or NSC45576.

Conclusions

These results demonstrate that the dopamine D₁ receptors are expressed on ASM and regulate smooth muscle force via cAMP activation of PKA, and offer a novel target for therapeutic relaxation of ASM.

【 授权许可】

   
2013 Mizuta et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Goto Y, Grace AA: The dopamine system and the pathophysiology of schizophrenia: a basic science perspective. Int Rev Neurobiol 2007, 78:41-68.
• [2]Pivonello R, Ferone D, Lombardi G, Colao A, Lamberts SW, Hofland LJ: Novel insights in dopamine receptor physiology. Eur J Endocrinol 2007, 156(Suppl 1):S13-S21.
• [3]Missale C, Nash SR, Robinson SW, Jaber M, Caron MG: Dopamine receptors: from structure to function. Physiol Rev 1998, 78(1):189-225.
• [4]Ozono R, O’Connell DP, Wang ZQ, Moore AF, Sanada H, Felder RA, Carey RM: Localization of the dopamine D1 receptor protein in the human heart and kidney. Hypertension 1997, 30(3 Pt 2):725-729.
• [5]Hussain T, Lokhandwala MF: Renal dopamine receptors and hypertension. Exp Biol Med (Maywood) 2003, 228(2):134-142.
• [6]Ricci A, Mignini F, Tomassoni D, Amenta F: Dopamine receptor subtypes in the human pulmonary arterial tree. Auton Autacoid Pharmacol 2006, 26(4):361-369.
• [7]Zizzo MG, Mule F, Mastropaolo M, Serio R: D1 receptors play a major role in the dopamine modulation of mouse ileum contractility. Pharmacol Res 2010, 61(5):371-378.
• [8]Neve KA, Seamans JK, Trantham-Davidson H: Dopamine receptor signaling. J Recept Signal Transduct Res 2004, 24(3):165-205.
• [9]Cabezas GA, Israili ZH, Velasco M: The actions of dopamine on the airways. Am J Ther 2003, 10(6):477-486.
• [10]Cabezas GA, Lezama Y, Vidal A, Velasco M: Inhaled dopamine induces bronchodilatation in patients with bronchial asthma. Int J Clin Pharmacol Ther 1999, 37(10):510-513.
• [11]Michoud MC, Amyot R, Jeanneret-Grosjean A: Dopamine effect on bronchomotor tone in vivo. Am Rev Respir Dis 1984, 130(5):755-758.
• [12]Advenier C, Saint-Aubin A, Mallard B, Boissier JR: Bronchopulmonary effects of dopamine in the guinea-pig. Arch Int Pharmacodyn Ther 1980, 243(2):261-274.
• [13]Cabezas GA, Velasco M: DA1 receptors modulation in rat isolated trachea. Am J Ther 2010, 17(3):301-305.
• [14]Mizuta K, Zhang Y, Xu D, Masaki E, Panettieri RA Jr, Emala CW: The dopamine D2 receptor is expressed and sensitizes adenylyl cyclase activity in airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 2012, 302(3):L316-L324.
• [15]Billington CK, Penn RB: Signaling and regulation of G protein-coupled receptors in airway smooth muscle. Respir Res 2003, 4:2.
• [16]Penn RB: Embracing emerging paradigms of G protein-coupled receptor agonism and signaling to address airway smooth muscle pathobiology in asthma. Naunyn Schmiedebergs Arch Pharmacol 2008, 378(2):149-169.
• [17]Roscioni SS, Maarsingh H, Elzinga CR, Schuur J, Menzen M, Halayko AJ, Meurs H, Schmidt M: Epac as a novel effector of airway smooth muscle relaxation. J Cell Mol Med 2011, 15(7):1551-1563.
• [18]Zieba BJ, Artamonov MV, Jin L, Momotani K, Ho R, Franke AS, Neppl RL, Stevenson AS, Khromov AS, Chrzanowska-Wodnicka M, et al.: The cAMP-responsive Rap1 guanine nucleotide exchange factor, Epac, induces smooth muscle relaxation by down-regulation of RhoA activity. J Biol Chem 2011, 286(19):16681-16692.
• [19]Panettieri RA, Murray RK, DePalo LR, Yadvish PA, Kotlikoff MI: A human airway smooth muscle cell line that retains physiological responsiveness. Am J Physiol 1989, 256(2 Pt 1):C329-C335.
• [20]Gosens R, Stelmack GL, Dueck G, McNeill KD, Yamasaki A, Gerthoffer WT, Unruh H, Gounni AS, Zaagsma J, Halayko AJ: Role of caveolin-1 in p42/p44 MAP kinase activation and proliferation of human airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 2006, 291(3):L523-L534.
• [21]Jooste E, Zhang Y, Emala CW: Rapacuronium preferentially antagonizes the function of M2 versus M3 muscarinic receptors in guinea pig airway smooth muscle. Anesthesiology 2005, 102(1):117-124.
• [22]Kebabian JW, DeNinno MP, Schoenleber R, MacKenzie R, Britton DR, Asin KE: A68930: a potent agonist specific for the dopamine D1 receptor. Neurochem Int 1992, 20(Suppl):157S-160S.
• [23]Torphy TJ: β-adrenoceptors, cAMP and airway smooth muscle relaxation: challenges to the dogma. Trends Pharmacol Sci 1994, 15(10):370-374.
• [24]Felder CC, McKelvey AM, Gitler MS, Eisner GM, Jose PA: Dopamine receptor subtypes in renal brush border and basolateral membranes. Kidney Int 1989, 36(2):183-193.
• [25]Lokhandwala MF, Amenta F: Anatomical distribution and function of dopamine receptors in the kidney. Faseb J 1991, 5(15):3023-3030.
• [26]Missale C, Pizzi M, Memo M, Picotti GB, Carruba MO, Spano PF: Postsynaptic D1 and D2 dopamine receptors are present in rabbit renal and mesenteric arteries. Neurosci Lett 1985, 61(1–2):207-211.
• [27]Drolet P, Bilodeau L, Chorvatova A, Laflamme L, Gallo-Payet N, Payet MD: Inhibition of the T-type Ca2+ current by the dopamine D1 receptor in rat adrenal glomerulosa cells: requirement of the combined action of the Gβγ protein subunit and cyclic adenosine 3′,5′-monophosphate. Mol Endocrinol 1997, 11(4):503-514.
• [28]Einstein R, Jordan H, Zhou W, Brenner M, Moses EG, Liggett SB: Alternative splicing of the G protein-coupled receptor superfamily in human airway smooth muscle diversifies the complement of receptors. Proc Natl Acad Sci USA 2008, 105(13):5230-5235.
• [29]Hack CJ: Integrated transcriptome and proteome data: the challenges ahead. Brief Funct Genom Proteomic 2004, 3(3):212-219.
• [30]Cox B, Kislinger T, Emili A: Integrating gene and protein expression data: pattern analysis and profile mining. Methods 2005, 35(3):303-314.
• [31]Griffin TJ, Gygi SP, Ideker T, Rist B, Eng J, Hood L, Aebersold R: Complementary profiling of gene expression at the transcriptome and proteome levels in Saccharomyces cerevisiae. Mol Cell Proteomics 2002, 1(4):323-333.
• [32]Tian Q, Stepaniants SB, Mao M, Weng L, Feetham MC, Doyle MJ, Yi EC, Dai H, Thorsson V, Eng J, et al.: Integrated genomic and proteomic analyses of gene expression in Mammalian cells. Mol Cell Proteomics 2004, 3(10):960-969.
• [33]Washburn MP, Koller A, Oshiro G, Ulaszek RR, Plouffe D, Deciu C, Winzeler E, Yates JR 3rd: Protein pathway and complex clustering of correlated mRNA and protein expression analyses in Saccharomyces cerevisiae. Proc Natl Acad Sci USA 2003, 100(6):3107-3112.
• [34]Ellis KE, Mistry R, Boyle JP, Challiss RA: Correlation of cyclic AMP accumulation and relaxant actions of salmeterol and salbutamol in bovine tracheal smooth muscle. Br J Pharmacol 1995, 116(5):2510-2516.
• [35]Hoiting BH, Meurs H, Schuiling M, Kuipers R, Elzinga CR, Zaagsma J: Modulation of agonist-induced phosphoinositide metabolism, Ca2+ signalling and contraction of airway smooth muscle by cyclic AMP-dependent mechanisms. Br J Pharmacol 1996, 117(3):419-426.
• [36]d’Emmanuele di Villa Bianca R, Sorrentino R, Roviezzo F, Imbimbo C, Palmieri A, De Dominicis G, Montorsi F, Cirino G, Mirone V: Peripheral relaxant activity of apomorphine and of a D1 selective receptor agonist on human corpus cavernosum strips. Int J Impot Res 2005, 17(2):127-133.
• [37]Grenader A, Healy DP: A68930 is a potent, full agonist at dopamine1 (D1) receptors in renal epithelial LLC-PK1 cells. Br J Pharmacol 1992, 106(2):229-230.
• [38]Penn RB, Benovic JL: Regulation of heterotrimeric G protein signaling in airway smooth muscle. Proc Am Thorac Soc 2008, 5(1):47-57.
• [39]Spicuzza L, Belvisi MG, Birrell MA, Barnes PJ, Hele DJ, Giembycz MA: Evidence that the anti-spasmogenic effect of the β-adrenoceptor agonist, isoprenaline, on guinea-pig trachealis is not mediated by cyclic AMP-dependent protein kinase. Br J Pharmacol 2001, 133(8):1201-1212.
• [40]Roscioni SS, Elzinga CR, Schmidt M: Epac: effectors and biological functions. Naunyn Schmiedebergs Arch Pharmacol 2008, 377(4–6):345-357.
• [41]Koike K, Yamashita Y, Horinouchi T, Yamaki F, Tanaka Y: cAMP-independent mechanism is significantly involved in β2-adrenoceptor-mediated tracheal relaxation. Eur J Pharmacol 2004, 492(1):65-70.
• [42]Tanaka Y, Horinouchi T, Koike K: New insights into β-adrenoceptors in smooth muscle: distribution of receptor subtypes and molecular mechanisms triggering muscle relaxation. Clin Exp Pharmacol Physiol 2005, 32(7):503-514.
• [43]Palmqvist M, Persson G, Lazer L, Rosenborg J, Larsson P, Lotvall J: Inhaled dry-powder formoterol and salmeterol in asthmatic patients: onset of action, duration of effect and potency. Eur Respir J 1997, 10(11):2484-2489.
• [44]Anderson GP, Linden A, Rabe KF: Why are long-acting beta-adrenoceptor agonists long-acting? Eur Respir J 1994, 7(3):569-578.
• [45]Szczuka A, Wennerberg M, Packeu A, Vauquelin G: Molecular mechanisms for the persistent bronchodilatory effect of the β2-adrenoceptor agonist salmeterol. Br J Pharmacol 2009, 158(1):183-194.
• [46]Johnson M: Molecular mechanisms of β2-adrenergic receptor function, response, and regulation. J Allergy Clin Immunol 2006, 117(1):18-24. quiz 25
• [47]DeNinno MP, Schoenleber R, MacKenzie R, Britton DR, Asin KE, Briggs C, Trugman JM, Ackerman M, Artman L, Bednarz L, Bhatt R, Curzon P, Gomez E, Kang CH, Stittsworth J, Kebabian JW: A68930: a potent agonist selective for the dopamine D1 receptor. Eur J Pharmacol 1991, 199(2):209-219.
• [48]Nergardh R, Oerther S, Fredholm BB: Differences between A 68930 and SKF 82958 could suggest synergistic roles of D1 and D5 receptors. Pharmacol Biochem Behav 2005, 82(3):495-505.