Direct inhibition of expressed cardiac l- and t-type calcium channels by igg from mothers whose children have congenital heart block.
BACKGROUND
Congenital heart block (CHB) is a disease that affects the offspring of mothers with autoimmune diseases. We recently reported that maternal sera containing antibodies against SSA/Ro and SSB/La ribonucleoproteins (positive IgG) inhibited L-type Ca current in isolated cardiac myocytes and induced sinus bradycardia in a murine model of CHB. The direct interaction of positive IgG with L-type Ca channel proteins and the possible inhibition of T-type Ca current that could account for the sinus bradycardia remain unknown.


RESULTS
The 2-electrode voltage-clamp technique was used to record currents via L-type (I(Ba)-alpha(1C) or I(Ba)-alpha(1C)+beta(2a)+alpha(2)/delta) and T-type (I(Ba)-alpha(1H)) Ca channels, Na channels (I(Na)-hH1), and K channels (I(Ks)-minK+KvLQT1) expressed in Xenopus oocytes. Positive IgG (350 microgram/mL) inhibited I(Ba)-alpha(1C) by 50.6+/-4.7% (P<0.01) and I(Ba)-alpha(1C)+beta(2a)+alpha(2)/delta by 50.9+/-4.2% (P<0.01); I(Ba)-alpha(1H) was reduced by 18.9+/-1.0% (P<0.01). Immunoblot data show cross-reactivity of positive IgG with alpha(1C) subunit. Pretreatment of oocytes with atropine (1 micromol/L) or acetylcholine (10 micromol/L) did not affect the inhibitory effect of IgG on I(Ba)-alpha(1C) and I(Ba)-alpha(1C)+beta(2a)+alpha(2)/delta (P<0.05). Positive IgG had no effect, however, on either I(Na)-hH1 or I(Ks)-minK+KvLQT1.


CONCLUSIONS
Positive IgG inhibited expressed L-type I:(Ba) and cross-reacted with the alpha(1C) subunit in Xenopus oocytes, providing strong evidence that maternal antibodies interact directly with the pore-forming alpha(1)-subunit of Ca channels. In addition, we show for the first time that positive IgG also inhibited T-type I(Ba) but not I(Na)-hH1 or I(Ks)-minK+KvLQT1. This could provide, in part, the ionic basis of sinus bradycardia reported in animal models of CHB and clinically in humans.
Molecular and Cellular Cardiology Program, New York Harbor Healthcare System and SUNY Health Science Center, Brooklyn, NY, USA.
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D000328:Adult; D000818:Animals; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D020747:Calcium Channels, T-Type / Q000187:drug effects / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D002648:Child; D003429:Cross Reactions; D004594:Electrophysiology; D005260:Female; D015870:Gene Expression; D006327:Heart Block / Q000151:congenital* / Q000235:genetics; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology*; D009035:Mothers; D009865:Oocytes; D015221:Potassium Channels / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D015222:Sodium Channels / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D014162:Transfection; D014982:Xenopus laevis
D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type; D007074:Immunoglobulin G; D015221:Potassium Channels; D015222:Sodium Channels