Structure-activity relations of the cardiac gap junction channel

David C. Spray, J. M. Burt

Research output: Contribution to journalArticle

240 Citations (Scopus)

Abstract

Cardiac gap junction channels play the important roles of synchronizing pacemaker cells and allowing impulse propagation along the conduction system and throughout the ventricular myocardium. These channels, which support current flow in both longitudinal and transverse directions, are permeable to anions and cations with radii < ~ 0.5 nm and in rat heart have unitary conductances on the order of 50 pS. This unitary conductance is consistent with channel geometry described by a right cylindrical pore with diameter large enough for the brilliantly fluorescent dye molecule lucifer yellow to pass between cells. These channels, like others in biological systems, are opened and closed by various treatments, a process termed gating. Cytoplasmic acidification reduces junctional conductance (g(j)), an effect that is apparently potentiated by elevated myoplasmic Ca ions. Reduced g(j) also occurs in response to a variety of lipophilic molecules, including halothane, heptanol, and unsaturated fatty acids; the mechanism of action may involve disruption of the protein-lipid microenvironment of the gap junction channel. Arachidonic acid uncouples, and this effect is partially, but incompletely, blocked by an inhibitor of the lipoxygenase metabolic pathways. Cyclooxygenase inhibitors have no protective effects. Certain cyclic nucleotides can rapidly increase g(j) [adenosine 3',5'-cyclic monophosphate (cAMP)] or slightly decrease it [guanosine 3',5'-cyclic monophosphate (cGMP)], and agents that use these cyclic nucleotides as second messengers (isoproterenol and perhaps carbachol, respectively) produce consistent effects. Agents expected to cause protein kinase C activation (tumor-promoting phorbol esters and diacylglycerol) increase g(j) rapidly. the gap junction protein from rat heart has been cloned and sequenced. From the primary sequence for the protein, plausible sites of action within the putative cytoplasmic domains are proposed for each of these treatments. In response to gating stimuli that close the channel (halothane, CO2, heptanol), unitary channel conductance is unchanged, suggested that these agents act by reducing open time probability. Together, these properties constitute the beginnings of our endeavor to define pharmacological agents that are potentially useful in therapeutic manipulation of synchronous discharge, conduction velocity, and isochronous wavefront propagation in cardiac tissue.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Cell Physiology
Volume258
Issue number2 27-2
StatePublished - 1990

Fingerprint

Heptanol
Gap Junctions
Cyclic Nucleotides
Halothane
Lipoxygenase Inhibitors
Connexins
Cyclooxygenase Inhibitors
Diglycerides
Reducing Agents
Cyclic GMP
Carbachol
Second Messenger Systems
Phorbol Esters
Metabolic Networks and Pathways
Unsaturated Fatty Acids
Fluorescent Dyes
Isoproterenol
Arachidonic Acid
Cyclic AMP
Protein Kinase C

Keywords

  • arrhythmias
  • connexin 43
  • gap junctional conductance
  • heart

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

Cite this

Structure-activity relations of the cardiac gap junction channel. / Spray, David C.; Burt, J. M.

In: American Journal of Physiology - Cell Physiology, Vol. 258, No. 2 27-2, 1990.

Research output: Contribution to journalArticle

@article{fa26c69530374b54be69ffe8a69ca3b2,
title = "Structure-activity relations of the cardiac gap junction channel",
abstract = "Cardiac gap junction channels play the important roles of synchronizing pacemaker cells and allowing impulse propagation along the conduction system and throughout the ventricular myocardium. These channels, which support current flow in both longitudinal and transverse directions, are permeable to anions and cations with radii < ~ 0.5 nm and in rat heart have unitary conductances on the order of 50 pS. This unitary conductance is consistent with channel geometry described by a right cylindrical pore with diameter large enough for the brilliantly fluorescent dye molecule lucifer yellow to pass between cells. These channels, like others in biological systems, are opened and closed by various treatments, a process termed gating. Cytoplasmic acidification reduces junctional conductance (g(j)), an effect that is apparently potentiated by elevated myoplasmic Ca ions. Reduced g(j) also occurs in response to a variety of lipophilic molecules, including halothane, heptanol, and unsaturated fatty acids; the mechanism of action may involve disruption of the protein-lipid microenvironment of the gap junction channel. Arachidonic acid uncouples, and this effect is partially, but incompletely, blocked by an inhibitor of the lipoxygenase metabolic pathways. Cyclooxygenase inhibitors have no protective effects. Certain cyclic nucleotides can rapidly increase g(j) [adenosine 3',5'-cyclic monophosphate (cAMP)] or slightly decrease it [guanosine 3',5'-cyclic monophosphate (cGMP)], and agents that use these cyclic nucleotides as second messengers (isoproterenol and perhaps carbachol, respectively) produce consistent effects. Agents expected to cause protein kinase C activation (tumor-promoting phorbol esters and diacylglycerol) increase g(j) rapidly. the gap junction protein from rat heart has been cloned and sequenced. From the primary sequence for the protein, plausible sites of action within the putative cytoplasmic domains are proposed for each of these treatments. In response to gating stimuli that close the channel (halothane, CO2, heptanol), unitary channel conductance is unchanged, suggested that these agents act by reducing open time probability. Together, these properties constitute the beginnings of our endeavor to define pharmacological agents that are potentially useful in therapeutic manipulation of synchronous discharge, conduction velocity, and isochronous wavefront propagation in cardiac tissue.",
keywords = "arrhythmias, connexin 43, gap junctional conductance, heart",
author = "Spray, {David C.} and Burt, {J. M.}",
year = "1990",
language = "English (US)",
volume = "258",
journal = "American Journal of Physiology - Renal Fluid and Electrolyte Physiology",
issn = "1931-857X",
publisher = "American Physiological Society",
number = "2 27-2",

}

TY - JOUR

T1 - Structure-activity relations of the cardiac gap junction channel

AU - Spray, David C.

AU - Burt, J. M.

PY - 1990

Y1 - 1990

N2 - Cardiac gap junction channels play the important roles of synchronizing pacemaker cells and allowing impulse propagation along the conduction system and throughout the ventricular myocardium. These channels, which support current flow in both longitudinal and transverse directions, are permeable to anions and cations with radii < ~ 0.5 nm and in rat heart have unitary conductances on the order of 50 pS. This unitary conductance is consistent with channel geometry described by a right cylindrical pore with diameter large enough for the brilliantly fluorescent dye molecule lucifer yellow to pass between cells. These channels, like others in biological systems, are opened and closed by various treatments, a process termed gating. Cytoplasmic acidification reduces junctional conductance (g(j)), an effect that is apparently potentiated by elevated myoplasmic Ca ions. Reduced g(j) also occurs in response to a variety of lipophilic molecules, including halothane, heptanol, and unsaturated fatty acids; the mechanism of action may involve disruption of the protein-lipid microenvironment of the gap junction channel. Arachidonic acid uncouples, and this effect is partially, but incompletely, blocked by an inhibitor of the lipoxygenase metabolic pathways. Cyclooxygenase inhibitors have no protective effects. Certain cyclic nucleotides can rapidly increase g(j) [adenosine 3',5'-cyclic monophosphate (cAMP)] or slightly decrease it [guanosine 3',5'-cyclic monophosphate (cGMP)], and agents that use these cyclic nucleotides as second messengers (isoproterenol and perhaps carbachol, respectively) produce consistent effects. Agents expected to cause protein kinase C activation (tumor-promoting phorbol esters and diacylglycerol) increase g(j) rapidly. the gap junction protein from rat heart has been cloned and sequenced. From the primary sequence for the protein, plausible sites of action within the putative cytoplasmic domains are proposed for each of these treatments. In response to gating stimuli that close the channel (halothane, CO2, heptanol), unitary channel conductance is unchanged, suggested that these agents act by reducing open time probability. Together, these properties constitute the beginnings of our endeavor to define pharmacological agents that are potentially useful in therapeutic manipulation of synchronous discharge, conduction velocity, and isochronous wavefront propagation in cardiac tissue.

AB - Cardiac gap junction channels play the important roles of synchronizing pacemaker cells and allowing impulse propagation along the conduction system and throughout the ventricular myocardium. These channels, which support current flow in both longitudinal and transverse directions, are permeable to anions and cations with radii < ~ 0.5 nm and in rat heart have unitary conductances on the order of 50 pS. This unitary conductance is consistent with channel geometry described by a right cylindrical pore with diameter large enough for the brilliantly fluorescent dye molecule lucifer yellow to pass between cells. These channels, like others in biological systems, are opened and closed by various treatments, a process termed gating. Cytoplasmic acidification reduces junctional conductance (g(j)), an effect that is apparently potentiated by elevated myoplasmic Ca ions. Reduced g(j) also occurs in response to a variety of lipophilic molecules, including halothane, heptanol, and unsaturated fatty acids; the mechanism of action may involve disruption of the protein-lipid microenvironment of the gap junction channel. Arachidonic acid uncouples, and this effect is partially, but incompletely, blocked by an inhibitor of the lipoxygenase metabolic pathways. Cyclooxygenase inhibitors have no protective effects. Certain cyclic nucleotides can rapidly increase g(j) [adenosine 3',5'-cyclic monophosphate (cAMP)] or slightly decrease it [guanosine 3',5'-cyclic monophosphate (cGMP)], and agents that use these cyclic nucleotides as second messengers (isoproterenol and perhaps carbachol, respectively) produce consistent effects. Agents expected to cause protein kinase C activation (tumor-promoting phorbol esters and diacylglycerol) increase g(j) rapidly. the gap junction protein from rat heart has been cloned and sequenced. From the primary sequence for the protein, plausible sites of action within the putative cytoplasmic domains are proposed for each of these treatments. In response to gating stimuli that close the channel (halothane, CO2, heptanol), unitary channel conductance is unchanged, suggested that these agents act by reducing open time probability. Together, these properties constitute the beginnings of our endeavor to define pharmacological agents that are potentially useful in therapeutic manipulation of synchronous discharge, conduction velocity, and isochronous wavefront propagation in cardiac tissue.

KW - arrhythmias

KW - connexin 43

KW - gap junctional conductance

KW - heart

UR - http://www.scopus.com/inward/record.url?scp=0025246161&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0025246161&partnerID=8YFLogxK

M3 - Article

C2 - 1689543

AN - SCOPUS:0025246161

VL - 258

JO - American Journal of Physiology - Renal Fluid and Electrolyte Physiology

JF - American Journal of Physiology - Renal Fluid and Electrolyte Physiology

SN - 1931-857X

IS - 2 27-2

ER -