Abstract
The σ receptors have been implicated in the regulation of the cardiovascular system, and σ-1 receptor transcripts have been found in parasympathetic intracardiac neurons. However, the cellular function of σ-1 receptors in these cells remains to be determined. Effects of σ 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 σ 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 σ 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 σ-1 receptor activation. Preincubation of neurons with the irreversible σ receptor antagonist metaphit blocked DTG-induced inhibition of K+ channels, confirming that the effect is mediated by σ receptor activation. Although bath application of σ 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 σ 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 σ-1 receptors are directly coupled to K+ channels in intracardiac neurons. Furthermore, activation of σ-1 receptors depresses the excitability of intracardiac neurons and is thus likely to block parasympathetic input to the heart.
Footnotes
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This study was supported by National Institutes of Health Grant R01 HL63247 (to J.C.) and American Heart Association Florida/Puerto Rico Affiliate Awards (grant-in-aid to J.C. and Predoctoral Fellowship to H.Z.). A preliminary report of some of these results has been presented in abstract form (Zhang and Cuevas, 2003).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.105.084152.
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ABBREVIATIONS: (+)-SKF-10,047, 2S-(2a,6a,11R*]-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2-propenyl)-2,6-methano-3-benzazocin-8-ol hydrochloride; DTG, 1,3-di-O-tolyguanidin; Kv, voltage-activated K+ channel; IK, voltage-activated K+ channel current; K(DR), delayed outwardly rectifying K+ channel; IM, M-current; GDP-β-S, guanosine 5′-O-(2-thiodiphosphate) trilithium salt; PSS, physiological saline solution; TTX, tetrodotoxin; GTP, GTP lithium salt; TEA, tetraethylammonium chloride; BK, large conductance K(Ca) channel; AHP, afterhyperpolarization; K(Ca), Ca2+-sensitive K+ channel; SK, small conductance K(Ca) channel; IK, intermediate conductance K(Ca) channel; BKi, fast inactivating BK current; BKs, noninactivating BK current; SM-21, (±)-tropanyl 2-(4-chlorophenoxy)butanoate maleate; BD-1047, N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine dihydrobromide; BD-1063, 1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine dihydrochloride.
- Received January 26, 2005.
- Accepted March 8, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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