Down‐regulation of non‐L‐, non‐N‐type (Q‐like) Ca<sup>2+</sup> channels by Lambert‐Eaton myasthenic syndrome (LEMS) antibodies in rat insulinoma RINm5F cells

Magnelli, V.; Grassi, Claudio; Parlatore, E.; Sher, Emanuele; Carbone, Emilio

doi:10.1016/0014-5793(96)00465-6

Cited by 18 publications

(12 citation statements)

References 24 publications

(36 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…LEMS IgG does not appear to cause a direct pharmacological block of the P͞Q-type VDCC either in transfected HEK293 cells or in rat Purkinje cells, which is in agreement with published studies (35,36). Divalent F(ab) 2 but not monovalent Fab fragments from LEMS IgG cause reduction in nerve-evoked release of acetylcholine and disruption of active zone particles at the presynaptic terminal of the neuromuscular junction, suggesting that LEMS IgG acts by cross-linking and down-regulating calcium channel numbers (37,38).…”

Section: Discussionsupporting

confidence: 93%

Human autoantibodies specific for the α _1A calcium channel subunit reduce both P-type and Q-type calcium currents in cerebellar neurons

Pinto

Gillard²,

Moss³

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

109

View full text Add to dashboard Cite

The pharmacological properties of voltagedependent calcium channel (VDCC) subtypes appear mainly to be determined by the ␣ 1 pore-forming subunit but, whether P-and Q-type VDCCs are encoded by the same ␣ 1 gene presently is unresolved. To investigate this, we used IgG antibodies to presynaptic VDCCs at motor nerve terminals that underlie muscle weakness in the autoimmune LambertEaton myasthenic syndrome (LEMS). We first studied their action on changes in intracellular free Ca 2؉ concentration [Ca 2؉ ] i in human embryonic kidney (HEK293) cell lines expressing different combinations of human recombinant VDCC subunits. Incubation for 18 h with LEMS IgG (2 mg͞ml) caused a significant dose-dependent reduction in the K ؉ -stimulated [Ca 2؉ ] i increase in the ␣ 1A cell line but not in the ␣ 1B , ␣ 1C , ␣ 1D , and ␣ 1E cell lines, establishing the ␣ 1A subunit as the target for these autoantibodies. Exploiting this specificity, we incubated cultured rat cerebellar neurones with LEMS IgG and observed a reduction in P-type current in Purkinje cells and both P-and Q-type currents in granule cells. These data are consistent with the hypothesis that the ␣ 1A gene encodes for the pore-forming subunit of both P-type and Q-type VDCCs.

show abstract

Section: Discussionsupporting

confidence: 93%

Human autoantibodies specific for the α _1A calcium channel subunit reduce both P-type and Q-type calcium currents in cerebellar neurons

Pinto

Gillard²,

Moss³

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

109

View full text Add to dashboard Cite

show abstract

“…1), as already reported in previous studies [20,22]. A progressive increase in current amplitude was usually observed for 1-2 min after the whole-cell configuration had been established.…”

Section: Effect Of No Donors On Hva Ba 2+ Currentssupporting

confidence: 61%

Ca 2+ channel inhibition induced by nitric oxide in rat insulinoma RINm5F cells

Grassi¹,

D’Ascenzo²,

Valente³

et al. 1999

Pfl�gers Archiv European Journal of Physiology

Self Cite

View full text Add to dashboard Cite

The effect of nitric oxide (NO) donors on high-voltage-activated Ca2+ channels in insulin-secreting RINm5F cells was investigated using the patch-clamp technique in the whole-cell configuration. Sodium nitroprusside (SNP, 2-400 microM) induced a dose-dependent reduction in Ba2+ currents with maximal inhibition of 58%. The IC50 for SNP was 45 microM. A different NO donor, (+/-)S-nitroso-N-acetylpenicillamine (SNAP, 500 microM), also produced a 50% decrease in current amplitude. When 200 microM SNP was administered together with the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidozoline-1-oxyl-3-oxide (carboxy-PTIO, 300 microM), the Ba2+ current inhibition was lowered to 7%. Administration of 500 microM 8-bromoguanosine 3':5'-cyclic monophosphate sodium salt (8-Br-cGMP) mimicked the effects of SNP, causing a comparable decrease (56%) in peak-current amplitude. When soluble guanylyl cyclase was blocked by 10 microM 1H-[1,2, 4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ), the inhibitory effect of 200 microM SNP was reduced from 39% to 15%. The SNP-induced current decrease was 36% of controls after the blockade of L-type Ca2+ channels and 30% in the presence of 2.5 microM omega-conotoxin-MVIIC. These data indicate that NO inhibits both L-type and P/Q-type Ca2+ channels in RINm5F cells, probably by an increase in the intracellular levels of cGMP. NO may then significantly influence the Ca2+-dependent release of hormones from secretory cells as well as that of neurotransmitters from nerve terminals.

show abstract

“…LEMS patients have high titres of anti‐VDCC auto‐antibodies, mainly anti‐P/Q‐type (∼ 90% of the patients) and anti‐N‐type VDCC (∼50% of the patients) antibodies. LEMS immunoglobulins (IgGs) have been shown to down‐regulate P/Q‐type Ca 2+ currents in different cell types (Magnelli et al ., 1996; Pinto et al ., 1998a, b). Passive transfer of LEMS IgGs into mice is sufficient to reproduce the human disease in animals (Lang et al ., 1983; Kim, 1985).…”

Section: Introductionmentioning

confidence: 99%

Calcium channel subtypes contributing to acetylcholine release from normal, 4‐aminopyridine‐treated and myasthenic syndrome auto‐antibodies‐affected neuromuscular junctions

Giovannini

Sher

Webster

et al. 2002

British J Pharmacology

View full text Add to dashboard Cite

1 Acetylcholine release at the neuromuscular junction relies on rapid, local and transient calcium increase at presynaptic active zones, triggered by the ion in¯ux through voltage-dependent calcium channels (VDCCs) clustered on the presynaptic membrane. Pharmacological investigation of the role of di erent VDCC subtypes (L-, N-, P/Q-and R-type) in spontaneous and evoked acetylcholine (ACh) release was carried out in adult mouse neuromuscular junctions (NMJs) under normal and pathological conditions. 2 o-Agatoxin IVA (500 nM), a speci®c P/Q-type VDCC blocker, abolished end plate potentials (EPPs) in normal NMJs. However, when neurotransmitter release was potentiated by the presence of the K + channel blocker 4-aminopyridine (4-AP), an o-agatoxin IVA-and o-conotoxin MVIICresistant component was detected. This resistant component was only partially sensitive to 1 mM oconotoxin GVIA (N-type VDCC blocker), but insensitive to any other known VDCC blockers. Spontaneous release was dependent only on P/Q-type VDCC in normal NMJs. However, in the presence of 4-AP, it relied on L-type VDCCs too. 3 ACh release from normal NMJs was compared with that of NMJs of mice passively injected with IgGs obtained from patients with Lambert-Eaton myasthenic syndrome (LEMS), a disorder characterized by a compromised neurotransmitter release. Di erently from normal NMJs, in LEMS IgGs-treated NMJs an o-agatoxin IVA-resistant EPP component was detected, which was only partially blocked by calciseptine (1 mM), a speci®c L-type VDCC blocker. 4 Altogether, these data demonstrate that multiple VDCC subtypes are present at the mouse NMJ and that a resistant component can be identi®ed under`pharmacological' and/or`pathological' conditions.

show abstract

Down‐regulation of non‐L‐, non‐N‐type (Q‐like) Ca²⁺ channels by Lambert‐Eaton myasthenic syndrome (LEMS) antibodies in rat insulinoma RINm5F cells

Abstract: The action exerted on non-L-,

Cited by 18 publications

References 24 publications

Human autoantibodies specific for the α _1A calcium channel subunit reduce both P-type and Q-type calcium currents in cerebellar neurons

Human autoantibodies specific for the α _1A calcium channel subunit reduce both P-type and Q-type calcium currents in cerebellar neurons

Ca 2+ channel inhibition induced by nitric oxide in rat insulinoma RINm5F cells

Calcium channel subtypes contributing to acetylcholine release from normal, 4‐aminopyridine‐treated and myasthenic syndrome auto‐antibodies‐affected neuromuscular junctions

Contact Info

Product

Resources

About

Down‐regulation of non‐L‐, non‐N‐type (Q‐like) Ca2+ channels by Lambert‐Eaton myasthenic syndrome (LEMS) antibodies in rat insulinoma RINm5F cells

Abstract: The action exerted on non-L-,

Cited by 18 publications

References 24 publications

Human autoantibodies specific for the α 1A calcium channel subunit reduce both P-type and Q-type calcium currents in cerebellar neurons

Human autoantibodies specific for the α 1A calcium channel subunit reduce both P-type and Q-type calcium currents in cerebellar neurons

Ca 2+ channel inhibition induced by nitric oxide in rat insulinoma RINm5F cells

Calcium channel subtypes contributing to acetylcholine release from normal, 4‐aminopyridine‐treated and myasthenic syndrome auto‐antibodies‐affected neuromuscular junctions

Contact Info

Product

Resources

About

Down‐regulation of non‐L‐, non‐N‐type (Q‐like) Ca²⁺ channels by Lambert‐Eaton myasthenic syndrome (LEMS) antibodies in rat insulinoma RINm5F cells

Human autoantibodies specific for the α _1A calcium channel subunit reduce both P-type and Q-type calcium currents in cerebellar neurons

Human autoantibodies specific for the α _1A calcium channel subunit reduce both P-type and Q-type calcium currents in cerebellar neurons