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Stimulating Camp Production in Human Corneal Epithelial Cells

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Stimulating Camp Production in Human Corneal Epithelial Cells Pharmacological Characterization of a Serotonin Receptor (5-HT7) Stimulating cAMP Production in Human Corneal Epithelial Cells Julie Y. Crider,1 Gary W. Williams,1 Colene D. Drace,1 Parvaneh Katoli,1 Michelle Senchyna,2 and Najam A. Sharif 1 PURPOSE. To study the mRNA and pharmacology of a serotonin potency data in the literature for the cloned human 5-HT7 (5-HT) receptor positively coupled to adenylyl cyclase in nor- receptor (r ϭ 0.88). mal, primary (P-CEPI), and immortalized human corneal epi- CONCLUSIONS. These collective data support the presence of a thelial cells (CEPI-17-CL4), by using numerous 5-HT agonists pharmacologically defined, adenylyl cyclase-coupled 5-HT7 re- and antagonists. To determine and compare cloned human ceptor in the CEPI-17-CL4 cells that may have relevance to 5-HT receptor binding affinities of compounds with their 7 physiological and/or pathologic functions of 5-HT7 receptors in functional potency data. the human cornea. (Invest Ophthalmol Vis Sci. 2003;44: METHODS. RT-PCR was used to detect the presence of an mRNA 4837–4844) DOI:10.1167/iovs.02-1292 for the human 5-HT7 receptor in CEPI-17-CL4 cells. Receptor- mediated production of cAMP in cultured cells was measured erotonin (5-HT) is a major neurotransmitter in the mamma- using an enzyme immunoassay. Compound binding affinities Slian central and peripheral nervous system.1–3 The recep- were determined using [3H]-lysergic acid diethylamide ([3H]- tors mediating the many diverse functions associated with 5-HT LSD) binding to cell membranes of human embryonic kidney are currently divided into seven subfamilies (5-HT1–7) which (HEK-293) cells expressing the cloned human 5-HT7 receptor. have all been cloned and pharmacologically characterized to various degrees.1–3 These membrane proteins, with the excep- RESULTS. RT-PCR revealed the presence of a 5-HT receptor 7 tion of the 5-HT receptor, represent a diverse group of G- mRNA in CEPI-17-CL4 cells. Normal P-CEPI cells generated 3 protein-coupled receptors. The 5-HT receptor subtypes (5- cAMP in response to 5-HT (Ϫlog EC ; pEC ϭ 7.6), 5-carbox- 1 50 50 HT , 5-HT , 5-HT , 5-HT , and 5-HT ) are negatively amidotryptamine (5-CT; pEC ϭ 7.8), 5-methoxy-tryptamine 1A 1B 1D 1E 1F 50 coupled to adenylyl cyclase. The 5-HT (5-HT , 5-HT , and (pEC ϭ 7.0) and 5-methoxy-dimethyl-tryptamine (pEC ϭ 2 2A 2B 50 50 5-HT ) receptor subtypes are coupled to phospholipase C and 5.7). In CEPI-17-CL4 cells, serotonergic agonists also stimulated 2C promote phosphoinositide (PI) turnover and release of intra- cAMP production with different potencies (pEC ): 5-CT 4 50 cellular calcium. The 5-HT receptor is a ligand-gated ion (7.4) Ͼ 5-HT (6.5) Ն 5-methoxy-tryptamine (6.1) Ͼ 5-methoxy- 3 Ն Ͻ ϭ ␣ channel, whereas the 5-HT4, 5-HT6, and 5-HT7 receptors are dimethyl-tryptamine (5.4) 8-OH-DPAT ( 5.0) -methyl- positively coupled to adenylyl cyclase through the G-protein 5-HT (Ͻ5.0). Various 5-HT receptor antagonists inhibited cAMP 5 GS. The 5-HT7 receptor can be distinguished from the 5-HT4 production induced by 5-CT in CEPI-17-CL4 cells with different and 5-HT receptors by its high-affinity and selectivity for Ͼ ϭ 6 potencies (pKi): methiothepin (8.5) mesulergine (8.1) 5-carboximidotryptamine (5-CT).6,7 Ͼ Ն ϭ metergoline (8.0) spiperone (7.4) clozapine (7.2) SB- The 5-HT receptor subtype has been cloned from human Ͼ Ͼ 7 258719 (7.2) mianserin (6.9) ketanserin (6.3). Antagonist and several other species8,9 and is the most recent serotonergic pKi values in P-CEPI cells were methiothepin (8.7), spiperone receptor subtype to be identified and characterized. The 5-HT7 (7.4) and SB-258719 (6.6). The rank order of affinity for dis- receptor exhibits low sequence homology with the other se- 3 placement of [ H]-LSD from the cloned human 5-HT7 receptor rotonin receptors that are positively coupled to adenylyl cy- was: methiothepin Ͼ ritanserin Ͼ mesulergine ϭ clozapine Ն clase. In the transmembrane domain, for instance, the 5-HT7 metergoline ϭ 5-HT Ͼ SB-258719 Ն spiperone Ͼ mianserin Ն receptor expresses approximately 39% homology with the ketanserin. The functional agonist and antagonist potency data 3 5-HT6 receptor and 46% with the 5-HT4 receptor. Three hu- obtained from CEPI-17-CL4 cells correlated well with cloned man 5-HT7 splice variants have been identified: the h5-HT7(a) human 5-HT receptor binding affinity data (r ϭ 0.69), with 7 (long form), h5-HT7(b) (short form), and 5-HT7(d), which differ P-CEPI cell functional data (r ϭ 0.85), and with functional only in their carboxyl terminus regions.10 These splice variants are pharmacologically similar in their coupling to adenylyl cyclase. The 5-HT7(a) and 5-HT7(b) receptor isoforms predomi- 11 1 nate in humans. Studies using the h5-HT7(a) splice variant From the Molecular Pharmacology Unit, Alcon Research, Ltd., 2ϩ 2 produced a stimulation of two Ca /calmodulin-sensitive ad- Fort Worth, Texas; and the School of Optometry, University of Wa- 2ϩ 12 terloo, Waterloo, Ontario, Canada. enylyl cyclase isoforms by increasing intracellular Ca . Hu- Supported by Alcon Research, Ltd. man 5-HT7 receptor splice variants are expressed in numerous Submitted for publication December 17, 2002; revised December peripheral tissues and in the central nervous system, some 3,13 17, 2002; accepted May 5, 2003. differentially. The 5-HT7 receptor is hypothesized to play a Disclosure: J.Y. Crider, Alcon Research, Ltd. (E, F); G.W. Wil- role in several physiological processes including control of liams, Alcon Research, Ltd. (E, F); C.D. Drace, Alcon Research, Ltd. circadian rhythms,14,15 the relaxation of smooth muscle,16 and (E, F); P. Katoli, Alcon Research, Ltd. (E, F); M. Senchyna, None; N.A. the pathophysiology of depression,17 migraine headaches,18 Sharif, Alcon Research, Ltd. (E, F) and schizophrenia.7 The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked “advertise- Despite the wealth of information about the many different ment” in accordance with 18 U.S.C. §1734 solely to indicate this fact. roles of 5-HT in the central and peripheral nervous systems Corresponding author: Naj Sharif, Molecular Pharmacology Unit, (see above), the role of 5-HT in the physiology and pathophys- Alcon Research, Ltd. (R2-19), 6201 South Freeway, Fort Worth, TX iology of the eye is less well explored and understood. The 76134-2099; [email protected]. demonstration of serotonergic innervation of the eye19 and the Investigative Ophthalmology & Visual Science, November 2003, Vol. 44, No. 11 Copyright © Association for Research in Vision and Ophthalmology 4837 Downloaded from jov.arvojournals.org on 09/27/2021 4838 Crider et al. IOVS, November 2003, Vol. 44, No. 11 presence of 5-HT in the aqueous humor20 has prompted some 3.5) was added for the termination of cAMP synthesis and cell lysis. ␮ ocular serotonergic studies. For instance, 5-HT1A receptors Finally, ice cold 0.1 M sodium acetate (225 L, pH 11.5–12.0) was have been found in the iris-ciliary body (ICB) of the rabbit,21 added to neutralize the samples before analysis by the EIA.27,28 3 and prejunctional 5-HT3 receptors modulating [ H]-norepi- nephrine release have been discovered in bovine and human cAMP Measurements ICBs.22 However, although early studies conducted in rabbit corneal tissues revealed the presence of a 5-HT receptor cou- cAMP production was measured using an EIA kit purchased from pled positively to adenylyl cyclase,23 the pharmacological char- Amersham Pharmacia Biotech (Piscataway, NJ). This assay was con- acterization of this rabbit receptor was not completed because ducted according to the package insert in an automated manner using a robotic workstation (Biomek 2000; Beckman Instruments, Fullerton, of the unavailability of suitable, potent, and selective 5-HT 27,28 receptor agonists and antagonists. We hypothesized that hu- CA). man corneal epithelium may also express such a 5-HT receptor and initiated functional studies on normal human corneal epi- Receptor Binding Studies thelial cells. However, because of the difficulty of obtaining Membranes from human embryonic kidney (HEK-293) cells expressing and propagating these cells, we also explored the use of a the cloned human 5-HT7 receptor (PerkinElmer Life Sciences, Boston, previously immortalized human corneal epithelial cell line MA) were diluted to 16 ␮g protein/mL in 4°C 50 mM Tris buffer (pH (CEPI-17-CL4) that exhibits many of the key genetic, pheno- 7.4). The membranes were resuspended using a tissue disrupter (Poly- typic, morphologic, pharmacological, and physiological fea- tron; Brinkman Instruments, Westbury, NY) equipped with a generator tures of the normal primary corneal epithelial cells and tis- (Ͻ20 seconds; PTA10TS). Drug dilutions were made in 10:10 dimethyl 24,25 sue. In the current communication, we describe the sulfoxide-ethanol (vol/vol), using the robotic workstation (model detailed pharmacological properties of the 5-HT receptor that 2000; Biomek). The diluted compounds (50 ␮L) were then added to a promoted the generation of cAMP in the human CEPI-17-CL4 96-well deep block. A volume of 400 ␮L of receptor preparation was cells, with confirmation of some data in normal human corneal manually added to the 96-well block. The workstation was then used to epithelial cells. In addition, we compared the functional po- add 50 ␮L(2nMfinal concentration) of [3H]-lysergic acid diethylamide tencies of the various serotonergic compounds determined in ([3H]-LSD; Perkin Elmer Life Sciences).
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