Effect of inherited abnormalities of calcium regulation on human neuromuscular transmission

Ricardo A Maselli, Wendy Books, Vanessa Dunne

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Synaptotagmins are abundant synaptic proteins that represent the best candidate for the calcium sensor at the nerve terminal. The pore-forming, voltage-sensing transmembrane alpha-1 subunit of the P/Q voltage-gated calcium channel (or Cav2.1) encoded by the CACNA1A gene is another major component of the process of action potential-evoked exocytosis at the adult mammalian neuromuscular junction. Defects of these proteins, in nonhuman species, result in severe disruption of rapid synaptic transmission. This paper investigates the molecular bases of inherited presynaptic deficits of neuromuscular transmission in humans. Patients with congenital presynaptic failure, including two patients with episodic ataxia type 2 (EA-2) due to CACNA1A mutations, were studied with muscle biopsy, microelectrode studies, electron microscopy, DNA amplification, and sequencing. All patients, including EA-2 patients, showed selective failure of the action potential-dependent release without reduction of the spontaneous release of neurotransmitter. In addition, patients with EA-2 showed partial blockade of neuromuscular transmission with the N-type blocker ω-conotoxin not seen in controls. The EM showed a varied degree of increased complexity of postsynaptic folds. Mutational analysis in candidate genes, including human synaptotagmin II, syntaxin 1A, synaptobrevin I, SNAP 25, CACNA1A, CACNB2, and Rab3A, was unrevealing. Although no mutations in candidate genes were found in patients with inborn presynaptic failure, functional and structural similarities between this group and patients with EA-2 due to CACNA1A mutations suggest a common pathogenic mechanism.

Original languageEnglish (US)
Pages (from-to)18-28
Number of pages11
JournalAnnals of the New York Academy of Sciences
Volume998
DOIs
StatePublished - 2003

Fingerprint

Genes
Calcium
Synaptotagmin II
Syntaxin 1
R-SNARE Proteins
Conotoxins
Synaptotagmins
Biopsy
Microelectrodes
Bioelectric potentials
Electric potential
Calcium Channels
Electron microscopy
Amplification
Neurotransmitter Agents
Muscle
Proteins
Mutation
Action Potentials
Defects

Keywords

  • Acetylcholine
  • CACNA1A mutations
  • Calcium
  • Inherited presynaptic deficits
  • Presynaptic congenital myasthenic syndromes
  • Synaptotagmins

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Effect of inherited abnormalities of calcium regulation on human neuromuscular transmission. / Maselli, Ricardo A; Books, Wendy; Dunne, Vanessa.

In: Annals of the New York Academy of Sciences, Vol. 998, 2003, p. 18-28.

Research output: Contribution to journalArticle

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