PASSIVE TRANSFER OF LAMBERT-EATON MYASTHENIC SYNDROME INDUCES DIHYDROPYRIDINE SENSITIVITY OF I-CA IN MOUSE MOTOR-NERVE TERMINALS

Mice were injected for 30 days with plasma from three patients with La mbert-Eaton Myasthenic Syndrome (LEMS). Recordings were made from the perineurial sheath of motor axon terminals of triangularis sterni musc le preparations. The objective was to characterize pharmacologically t he identity of kinetically distinct, defined potential changes associa ted with motor nerve terminal Ca2+ currents (I-Ca) that were affected by LEMS autoantibodies. I-Ca elicited at 0.01 Hz were significantly re duced in amplitude by similar to 35% of control in LEMS-treated nerve terminals. During 10-Hz stimulation, I-Ca amplitude was unchanged In L EMS-treated motor nerve terminals, but was depressed in control. Durin g 20- or 100-Hz trains, facilitation of I-Ca occurred in LEMS-treated nerve terminals whereas in control, no facilitation occurred during th e trains at 20 Hz and marked depression occurred at 100 Hz. Saturation for amplitude and duration of I-Ca in control terminals occurred at 2 and 4-6 mM extracellular Ca2+, respectively; in LEMS-treated terminal s, the extracellular Ca2+ concentration had to increase by two to thre e times of control to cause saturation. Amplitude of the two component s of I-Ca observed when the preparation was exposed to 50 mu M 3,4-dia minopyridine and 1 mM tetraethylammonium were both reduced by LEMS pla sma treatment. The fast component (I-Ca,I-f) was reduced by 35%, where as the slow component (I-Ca,I-s) was reduced by 37%. omega-Agatoxin IV A (omega-Aga-IVA, 0.15 mu M) and omega-conotoxin-MVIIC (omega-CTx-MVII C; 5 mu M) completely blocked I-Ca in central motor nerve terminals. T he same concentrations of toxins were 20-30% less effective in blockin g I-Ca in LEMS-treated terminals. The residual I-Ca remaining after tr eatment with omega-Aga-IVA or omega-CTx-MVIIC was blocked by 10 mu M n ifedipine and 10 mu M Cd2+. Thus LEMS plasma appears to downregulate o mega-Aga-IVA-sensitive (P-type) and/or omega-CTx-MVIIC-sensitive (Q-ty pe) Ca2+ channels in murine motor nerve terminals, whereas dihydropyri dine (DHP)-sensitive (L-type) Ca2+ channels are unmasked in these term inals. Acute exposure (90 min) of rat forebrain synaptosomes to LEMS i mmunoglobulins (Igs; 4 mg/ml) did not alter the binding of [H-3]-nitre ndipine or [I-125]-omega-conotoxin-GVIA (-omega-CgTx GVIA) when compar ed with synaptosomes incubated with an equivalent concentration of con trol Igs. Conversely LEMS Igs significantly decreased the B-max for [H -3]-verapamil to similar to 45% of control. The apparent affinity of v erapamil (K-D) for the remaining receptors was not significantly alter ed. Thus acute exposure of isolated central nerve terminals to LEMS Ig s does not increase DHP sensitivity, whereas it reduces the number of binding sites for verapamil but not for nitrendipine or omega-CgTx-GVI A. These results suggest that chronic but not acute exposure to LEMS I gs either upregulates or unmasks DHP-sensitive Ca2+ channels in motor nerve endings.