The pharmacological receptor of cardiac glycosides is the Na$^+$/K$^+$-ATPase
which consists of a catalytic alpha (M(r) = 112,000) and glycosylated
beta (M(r) = 35,000) subunit. The enzyme is responsible for the vectorial
transport across the sarcolemma of three Na$^+$ ions outward
and two K$^+$ ions inward against their electrochemical gradient.
Specific inhibition of the Na$^+$ pump by digitalis induces a
positive inotropic effect by increasing the intracellular Na$^+$
concentration which in turn induces an increase in the intracellular
Ca$^2+$ concentration by the Na$^+$/Ca$^2+$ exchange
and an increase in the Ca$^2+$ pool of the sarcoplasmic reticulum;
toxic effects are observed at higher doses of cardiac glycosides
leading to spontaneous calcium release from the sarcoplasmic reticulum.
Three isoforms of the alpha catalytic subunit have been identified
by molecular cloning. They share a high homology in the deduced amino
acid sequence with eight transmembrane domains. The ouabain binding
domain is located on the extracellular side and ouabain sensitivity
depends mainly on the two residues at the border of the first extracellular
domain. The isoforms differed by their ouabain sensitivity, are expressed
in a tissue-specific and hormonally-regulated manner. Moreover, expression
of the isoforms and their ouabain sensitivity vary from species to
species with an alpha 1 isoform of very low affinity being the major
isoform (80\%) in the adult rat heart and an alpha 1 isoform of high
affinity representing 50\% of total alpha mRNA abundance in the human
heart. Therefore the effect of digitalis on the heart depends mainly
on the isoform which is expressed and on the regulation of their
expression according to age, hormonal influence and pathology.
%0 Journal Article
%1 Char_1993_79
%A Charlemagne, D.
%D 1993
%J Herz
%K /&/ ATPase, Animals; Channels, Contraction, Digitalis Enzymologic, Expression Gene Glycosides, Humans; Ion Isoenzymes, Myocardial Regulation, Relationship Sodium-Potassium-Exchanging Structure-Activity antagonists drug effects/physiology; effects; inhibitors/genetics/physiology; inhibitors/physiology; pharmacology;
%N 2
%P 79--85
%T Molecular and cellular level of action of digitalis.
%V 18
%X The pharmacological receptor of cardiac glycosides is the Na$^+$/K$^+$-ATPase
which consists of a catalytic alpha (M(r) = 112,000) and glycosylated
beta (M(r) = 35,000) subunit. The enzyme is responsible for the vectorial
transport across the sarcolemma of three Na$^+$ ions outward
and two K$^+$ ions inward against their electrochemical gradient.
Specific inhibition of the Na$^+$ pump by digitalis induces a
positive inotropic effect by increasing the intracellular Na$^+$
concentration which in turn induces an increase in the intracellular
Ca$^2+$ concentration by the Na$^+$/Ca$^2+$ exchange
and an increase in the Ca$^2+$ pool of the sarcoplasmic reticulum;
toxic effects are observed at higher doses of cardiac glycosides
leading to spontaneous calcium release from the sarcoplasmic reticulum.
Three isoforms of the alpha catalytic subunit have been identified
by molecular cloning. They share a high homology in the deduced amino
acid sequence with eight transmembrane domains. The ouabain binding
domain is located on the extracellular side and ouabain sensitivity
depends mainly on the two residues at the border of the first extracellular
domain. The isoforms differed by their ouabain sensitivity, are expressed
in a tissue-specific and hormonally-regulated manner. Moreover, expression
of the isoforms and their ouabain sensitivity vary from species to
species with an alpha 1 isoform of very low affinity being the major
isoform (80\%) in the adult rat heart and an alpha 1 isoform of high
affinity representing 50\% of total alpha mRNA abundance in the human
heart. Therefore the effect of digitalis on the heart depends mainly
on the isoform which is expressed and on the regulation of their
expression according to age, hormonal influence and pathology.
@article{Char_1993_79,
abstract = {The pharmacological receptor of cardiac glycosides is the {N}a$^{+}$/{K}$^{+}$-ATPase
which consists of a catalytic alpha (M(r) = 112,000) and glycosylated
beta (M(r) = 35,000) subunit. The enzyme is responsible for the vectorial
transport across the sarcolemma of three {N}a$^{+}$ ions outward
and two {K}$^{+}$ ions inward against their electrochemical gradient.
Specific inhibition of the {N}a$^{+}$ pump by digitalis induces a
positive inotropic effect by increasing the intracellular {N}a$^{+}$
concentration which in turn induces an increase in the intracellular
{C}a$^{2+}$ concentration by the {N}a$^{+}$/{C}a$^{2+}$ exchange
and an increase in the {C}a$^{2+}$ pool of the sarcoplasmic reticulum;
toxic effects are observed at higher doses of cardiac glycosides
leading to spontaneous calcium release from the sarcoplasmic reticulum.
Three isoforms of the alpha catalytic subunit have been identified
by molecular cloning. They share a high homology in the deduced amino
acid sequence with eight transmembrane domains. The ouabain binding
domain is located on the extracellular side and ouabain sensitivity
depends mainly on the two residues at the border of the first extracellular
domain. The isoforms differed by their ouabain sensitivity, are expressed
in a tissue-specific and hormonally-regulated manner. Moreover, expression
of the isoforms and their ouabain sensitivity vary from species to
species with an alpha 1 isoform of very low affinity being the major
isoform (80\%) in the adult rat heart and an alpha 1 isoform of high
affinity representing 50\% of total alpha mRNA abundance in the human
heart. Therefore the effect of digitalis on the heart depends mainly
on the isoform which is expressed and on the regulation of their
expression according to age, hormonal influence and pathology.},
added-at = {2009-06-03T11:20:58.000+0200},
author = {Charlemagne, D.},
biburl = {https://www.bibsonomy.org/bibtex/2b029d3127c4932e8787df9c67d855bf2/hake},
description = {The whole bibliography file I use.},
institution = {INSERM, Hopital Lariboisière, Paris, France.},
interhash = {61c325f0b8896ada120aa3687c695d1e},
intrahash = {b029d3127c4932e8787df9c67d855bf2},
journal = {Herz},
keywords = {/&/ ATPase, Animals; Channels, Contraction, Digitalis Enzymologic, Expression Gene Glycosides, Humans; Ion Isoenzymes, Myocardial Regulation, Relationship Sodium-Potassium-Exchanging Structure-Activity antagonists drug effects/physiology; effects; inhibitors/genetics/physiology; inhibitors/physiology; pharmacology;},
month = Apr,
number = 2,
pages = {79--85},
pmid = {7684015},
timestamp = {2009-06-03T11:21:08.000+0200},
title = {Molecular and cellular level of action of digitalis.},
volume = 18,
year = 1993
}