Cardiac arrhythmia (Coworkers,
Dr. Dr. Marco Weiergräber, Renate Clemens, Margit Henry):
Arrhythmia in isolated prenatal hearts after ablation of the Cav2.3 (a1E) subunit of voltage-gated Ca2+ channels (Lu et al., 2004).
A voltage-gated calcium channel containing Cav2.3e (a1Ee) as the ion conducting
pore has recently been detected in rat heart (Weiergräber et al., 2000).
Functional evidence for this Ca2+ channel to be involved in the regulation of
heart beating, besides L- and T-type channels, was derived from murine embryos
where the gene for Cav1.2 had been ablated (Seisenberger et al., 2000). The
remaining „L-type like“ current component was not related to recombinant splice
variants of Cav1.3 containing channels. As recombinant Cav2.3 channels from rat
were reported to be weakly dihydropyridine sensitive (Stephens et al., 1997),
the spontaneous activity of the prenatal hearts from Cav2.3(-|-) mice was
compared to that of Cav2.3(+|+) control animals to investigate if Cav2.3 could
represent such a L-type like Ca2+ channel. The spontaneous activity of murine
embryonic hearts was recorded by using a multielectrode array. Between day 9.5
p.c. to 12.5 p.c., the beating frequency of isolated embryonic hearts from
Cav2.3-deficient mice did not differ significantly from control mice but the
coefficient of variation within individual episodes was more than four-fold
increased in Cav2.3-deficient mice indicating arrhythmia. In isolated hearts
from wild type mice, arrhythmia was induced by superfusion with a solution
containing 200 nM SNX-482, a blocker of some R-type voltage gated Ca2+ channels,
suggesting that R-type channels containing the splice variant Cav2.3e as ion
conducting pore stabilize a more regular heart beat in prenatal mice.
Ablation of Cav2.3 / E-type voltage-gated calcium channel results in cardiac arrhythmia and altered autonomic control within the murine cardiovascular system (Weiergräber et al., 2004).
Cardia
arrhythmia (PDF)
Voltage-gated calcium channels are key components in cardiac electrophysiology.
We demonstrate that Cav2.3 is expressed in mouse and human heart and
that mice lacking the Cav2.3 voltage-gated calcium channel exhibit
severe alterations in cardiac function.
Amplified cDNA fragments from murine heart and single cardiomyocytes reveal the
expression of three different Cav2.3 splice variants. The ablation of
Cav2.3 was found to be accompanied with a compensatory upregulation
of the Cav3.1 T-type calcium channel, while other voltage-gated
calcium channels remained unaffected. Telemetric ECG recordings from Cav2.3
deficient mice displayed subsidiary escape rhythm, altered atrial activation
patterns, atrioventricular conduction disturbances and alteration in
QRS-morphology. Furthermore, time domain analysis of heart rate variability
(HRV) in Cav2.3(-|-) mice exhibited significant increase in heart
rate as well as in the coefficient of variance (CV) compared to control mice.
Administration of atropin/propranolol revealed that increased heart rate was due
to enhanced sympathetic tonus and that partial decrease of CV in Cav2.3(-|-)
mice after autonomic block was in accordance with a complete abolishment of 2nd
degree atrioventricular block. However, escape rhythms, atrial activation
disturbances and QRS-dysmorphology remained unaffected, indicating that these
are intrinsic cardiac features in Cav2.3(-|-) mice. We conclude, that
the expression of Cav2.3 is essential for normal impulse generation
and conduction in murine heart.
Referneces, “arrhythmia”:
Lu, Z.-L., Pereverzev, A., Liu, H.-L., Weiergraber, M., Henry, M., Krieger, A., Smyth, N., Hescheler, J., and Schneider, T. Arrhythmia in isolated prenatal hearts after ablation of the Cav2.3 (a1E) subunit of voltage-gated Ca2+ channels. Cellular Physiology and Biochemistry 14, 11-22. 2004.
Seisenberger C, Specht V, Welling A, Platzer J, Pfeifer A, Kuhbandner S, Striessnig J, Klugbauer N, Feil R, Hofmann F (2000) Functional embryonic cardiomyocytes after disruption of the L-type alpha 1C (Cav1.2) calcium channel gene in the mouse. J Biol Chem 275: 39193-39199.
Stephens GJ, Page KM, Burley JR, Berrow NS, Dolphin AC (1997) Functional expression of rat brain cloned alpha1E calcium channels in COS-7 cells. Pflugers Arch 433: 523-532.
Weiergräber M, Pereverzev A, Vajna R, Henry M, Schramm M, Nastainczyk W, Grabsch H, Schneider T (2000) Immunodetection of a1E voltage-gated Ca2+ channel in chromogranin-positive muscle cells of rat heart, and in distal tubules of human kidney. J Histochem Cytochem 48: 807-819.
Weiergräber Marco, Margit Henry, Michael Südkamp, Ernst-Rainer de Vivie, Jürgen
Hescheler, Toni Schneider (2004) Ablation of Cav2.3 / E-type
voltage-gated calcium channel results in cardiac arrhythmia and altered
autonomic control within the murine cardiovascular system. Basic Res.
Cardiol., in press.