23 research outputs found
Cardiac muscle cell interaction: from microanatomy to the molecular make-up of the gap junction
Electrical coupling between cardiac muscle
cells is mediated by specialised sites of plasma
membrane interaction termed gap junctions, one of three
types of intercellular junction of the cardiac intercalated
disk. Gap junctions consist of clusters of plasma
membrane channels directly linking the cytoplasmic
compartments of neighbouring cells. Gap-junctional
channels are constructed from connexins, a multigene
family of conserved proteins. The principal connexin
isoform of the mammalian heart is connexin43; other
connexins, notably connexin40, connexin45 and
connexin37, are also expressed but in smaller quantities.
Antibodies directed against unique sequences of these
molecules allow investigation of the role of gap
junctions and their component connexins in relation to
the electrophysiological properties of the healthy and
diseased heart. Confocal laser scanning microscopy of
working ventricular myocytes immunolabelled with anticonnexin43
antibodies permits highly sensitive detection
of gap junctions, allowing detailed analysis of the spatial
distribution of the conduction pathways from the leve1 of
the cell to that of the tissue as a whole. Gap junction
distribution, number and regional variations in the type
of connexin expressed al1 contribute to the uniform
anisotropic pattern of impulse spread characteristic of
normal myocardium and the orderly, sequential
contraction of the cardiac chambers. Connexin40 is
preferentially expressed by myocytes of the atrioventricular conduction system and represents a
specialisation facilitating fast conduction, allowing rapid
distribution of the impulse throughout the working
ventricle. Two major abnormalities in connexin43 gap
junctions are detected in human ischaemic heart disease.
First, at border zones adjacent to infarct scars, zones
which are particularly prone to re-entry arrhythmia, there
is marked disruption of the usual ordered distribution
pattem of gap junctions. Second, a widespread downregulation
of connexin43 gap junctions occurs in myocardium distant from the infarct, a change that is
also found in the hypertrophic (non-ischaemic) heart.
Consequent localised heterogeneous conduction and
reduced conduction velocity provide an explanation for
the genesis of re-entry arrhythmias. A current working
hypothesis is that reduction in connexin43 gap junctions
is a general pathogenetic feature of cardiac disease
which predisposes the heart to arrhythrnia, and that this
reduction may form part of a wider pattem of alteration
in the levels of other connexin isoforms