Structure-activity relations of the cardiac gap junction channel

D. C. Spray, J. M. Burt

Research output: Contribution to journalReview article

241 Scopus citations

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)
Pages (from-to)C195-C205
JournalAmerican Journal of Physiology - Cell Physiology
Volume258
Issue number2 27-2
StatePublished - Mar 20 1990

Keywords

  • arrhythmias
  • connexin 43
  • gap junctional conductance
  • heart

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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