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8-hydroxy-2-(di-n-propylamino)tetralin-responsive 5-hydroxytryptamine4-like receptor expressed in bovine pulmonary artery smooth muscle cells.

Publication ,  Journal Article
Becker, BN; Gettys, TW; Middleton, JP; Olsen, CL; Albers, FJ; Lee, SL; Fanburg, BL; Raymond, JR
Published in: Mol Pharmacol
November 1992

Bovine pulmonary artery smooth muscle (SM) cells express a novel 5-hydroxytryptamine (5-HT) (5-HT4-like) receptor coupled to cAMP accumulation. cAMP radioimmunoassay established the agonist and antagonist profiles of this receptor. 5-HT (EC50 = 91 +/- 33 nM) and 5-methoxytryptamine were equipotent at the SM cell 5-HT receptor and both were more potent than 5-carboxamidotryptamine. Other tryptamine derivatives were less potent but remained full agonists. These findings are consistent with previous reports regarding 5-HT4 and 5-HT4-like receptors in the central nervous system. The most potent antagonists were the antidepressant compounds nortriptyline (IC50 = 177 +/- 153 nM) and zimelidine (IC50 = 202 +/- 101 nM). The 5-HT3 and 5-HT4 antagonist 3-tropanyl-indole-3-carboxylate (ICS 205-930) was also a competitive antagonist at this 5-HT4-like receptor (pA2 = 6.3). Antagonist affinities differed slightly at the SM cell receptor, compared with other 5-HT4 and 5-HT4-like receptors in the central nervous system. Nonetheless, the SM cell 5-HT4-like receptor displayed the same differential antagonist potencies as reported for these other receptors (ICS 205-930 > MDL 72222 and mianserin > ketanserin). 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was the most potent agonist for this 5-HT4-like receptor (EC50 = 6.4 +/- 3.4 nM). 8-OH-DPAT-induced cAMP accumulation could be blocked by ICS 205-930 but not by the 5-HT1A antagonist 1-(2-methoxyphenyl)-4-[4-(2-pthalimido)butyl]piperazine hydrobromide, distinguishing the SM cell 5-HT receptor from 5-HT1A receptors. The mechanism of 5-HT-stimulated cAMP production was also investigated. First, GTP augmented basal and 5-HT-stimulated cAMP accumulation. Second, antisera to the carboxyl terminus of the alpha subunit of Gs, attenuated 5-HT-mediated adenylate cyclase activation. This established that 5-HT-stimulated cAMP accumulation in SM cells required GS. These findings suggest that SM cells express a novel 5-HT4-like receptor positively coupled to adenylate cyclase. An unexpected finding was that 8-OH-DPAT is a potent partial agonist. These studies suggest that there may be heterogeneity among 5-HT4-like receptors.

Duke Scholars

Published In

Mol Pharmacol

ISSN

0026-895X

Publication Date

November 1992

Volume

42

Issue

5

Start / End Page

817 / 825

Location

United States

Related Subject Headings

  • Type C Phospholipases
  • Tropisetron
  • Serotonin Antagonists
  • Serotonin
  • Receptors, Serotonin
  • Radioimmunoassay
  • Pulmonary Artery
  • Phosphatidylinositols
  • Pharmacology & Pharmacy
  • Muscle, Smooth, Vascular
 

Citation

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Becker, B. N., Gettys, T. W., Middleton, J. P., Olsen, C. L., Albers, F. J., Lee, S. L., … Raymond, J. R. (1992). 8-hydroxy-2-(di-n-propylamino)tetralin-responsive 5-hydroxytryptamine4-like receptor expressed in bovine pulmonary artery smooth muscle cells. Mol Pharmacol, 42(5), 817–825.
Becker, B. N., T. W. Gettys, J. P. Middleton, C. L. Olsen, F. J. Albers, S. L. Lee, B. L. Fanburg, and J. R. Raymond. “8-hydroxy-2-(di-n-propylamino)tetralin-responsive 5-hydroxytryptamine4-like receptor expressed in bovine pulmonary artery smooth muscle cells.Mol Pharmacol 42, no. 5 (November 1992): 817–25.
Becker BN, Gettys TW, Middleton JP, Olsen CL, Albers FJ, Lee SL, et al. 8-hydroxy-2-(di-n-propylamino)tetralin-responsive 5-hydroxytryptamine4-like receptor expressed in bovine pulmonary artery smooth muscle cells. Mol Pharmacol. 1992 Nov;42(5):817–25.
Becker BN, Gettys TW, Middleton JP, Olsen CL, Albers FJ, Lee SL, Fanburg BL, Raymond JR. 8-hydroxy-2-(di-n-propylamino)tetralin-responsive 5-hydroxytryptamine4-like receptor expressed in bovine pulmonary artery smooth muscle cells. Mol Pharmacol. 1992 Nov;42(5):817–825.

Published In

Mol Pharmacol

ISSN

0026-895X

Publication Date

November 1992

Volume

42

Issue

5

Start / End Page

817 / 825

Location

United States

Related Subject Headings

  • Type C Phospholipases
  • Tropisetron
  • Serotonin Antagonists
  • Serotonin
  • Receptors, Serotonin
  • Radioimmunoassay
  • Pulmonary Artery
  • Phosphatidylinositols
  • Pharmacology & Pharmacy
  • Muscle, Smooth, Vascular