QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.105.084152v1 313/3/1387    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhang, H. Articles by Cuevas, J. Search for Related Content PubMed PubMed Citation Articles by Zhang, H. Articles by Cuevas, J.

NEUROPHARMACOLOGY

Receptor Activation Blocks Potassium Channels and Depresses Neuroexcitability in Rat Intracardiac Neurons

Department of Pharmacology and Therapeutics, University of South Florida College of Medicine, Tampa, Florida

The receptors have been implicated in the regulation of the cardiovascular system, and -1 receptor transcripts have been found in parasympathetic intracardiac neurons. However, the cellular function of -1 receptors in these cells remains to be determined. Effects of receptor activation on voltage-activated K⁺ channels and action potential firing were studied in isolated intracardiac neurons using whole-cell patch-clamp recording techniques. Activation of receptors reversibly blocked delayed outwardly rectifying potassium channels, large conductance Ca²⁺-sensitive K⁺ channels, and the M-current with maximal inhibition >80%. The inhibition of K⁺ channels by ligands was dose-dependent, and the rank order potency of (+)-pentazocine > ibogaine > 1,3-di-O-tolyguanidin (DTG) suggests that the effect is mediated by -1 receptor activation. Preincubation of neurons with the irreversible receptor antagonist metaphit blocked DTG-induced inhibition of K⁺ channels, confirming that the effect is mediated by receptor activation. Although bath application of ligands depolarized intracardiac neurons, the number of action potentials fired by the cells in response to depolarizing current pulses was decreased in the presence of these drugs. Neither dialysis of the neurons nor application of intracellular 5'-O-(2-thiodiphosphate) trilithium salt inhibited the effect of receptors on K⁺ channels, which suggests that the signal transduction pathway does not involve a diffusible cytosolic second messenger or a G protein. Together, these data suggest that -1 receptors are directly coupled to K⁺ channels in intracardiac neurons. Furthermore, activation of -1 receptors depresses the excitability of intracardiac neurons and is thus likely to block parasympathetic input to the heart.

Address correspondence to: Dr. Javier Cuevas, Department of Pharmacology and Therapeutics, University of South Florida College of Medicine, 12901 Bruce B. Downs Blvd., MDC 9, Tampa, FL 33612-4799. E-mail: jcuevas{at}hsc.usf.edu

This article has been cited by other articles:

				M. Johannessen, S. Ramachandran, L. Riemer, A. Ramos-Serrano, A. E. Ruoho, and M. B. Jackson Voltage-gated sodium channel modulation by {sigma}-receptors in cardiac myocytes and heterologous systems Am J Physiol Cell Physiol, May 1, 2009; 296(5): C1049 - C1057. [Abstract] [Full Text] [PDF]

				D. Fontanilla, M. Johannessen, A. R. Hajipour, N. V. Cozzi, M. B. Jackson, and A. E. Ruoho The Hallucinogen N,N-Dimethyltryptamine (DMT) Is an Endogenous Sigma-1 Receptor Regulator Science, February 13, 2009; 323(5916): 934 - 937. [Abstract] [Full Text] [PDF]

				Y. Herrera, C. Katnik, J. D. Rodriguez, A. A. Hall, A. Willing, K. R. Pennypacker, and J. Cuevas {sigma}-1 Receptor Modulation of Acid-Sensing Ion Channel a (ASIC1a) and ASIC1a-Induced Ca2+ Influx in Rat Cortical Neurons J. Pharmacol. Exp. Ther., November 1, 2008; 327(2): 491 - 502. [Abstract] [Full Text] [PDF]

				K. T. Tchedre, R.-Q. Huang, A. Dibas, R. R. Krishnamoorthy, G. H. Dillon, and T. Yorio Sigma-1 Receptor Regulation of Voltage-Gated Calcium Channels Involves a Direct Interaction Invest. Ophthalmol. Vis. Sci., November 1, 2008; 49(11): 4993 - 5002. [Abstract] [Full Text] [PDF]

				L. Monassier, B. Manoury, C. Bellocq, J. Weissenburger, H. Greney, D. Zimmermann, J.-D. Ehrhardt, P. Jaillon, I. Baro, and P. Bousquet {sigma}2-Receptor Ligand-Mediated Inhibition of Inwardly Rectifying K+ Channels in the Heart J. Pharmacol. Exp. Ther., July 1, 2007; 322(1): 341 - 350. [Abstract] [Full Text] [PDF]

				C. Katnik, W. R. Guerrero, K. R. Pennypacker, Y. Herrera, and J. Cuevas Sigma-1 Receptor Activation Prevents Intracellular Calcium Dysregulation in Cortical Neurons during in Vitro Ischemia J. Pharmacol. Exp. Ther., December 1, 2006; 319(3): 1355 - 1365. [Abstract] [Full Text] [PDF]