Effect of inherited abnormalities of calcium regulation on human neuromuscular transmission

Ann N Y Acad Sci. 2003 Sep:998:18-28. doi: 10.1196/annals.1254.004.


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 Ca(v)2.1) 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 omega-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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Adolescent
  • Adult
  • Ataxia / complications
  • Ataxia / genetics
  • Ataxia / physiopathology
  • Base Sequence
  • Calcium / deficiency*
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels / genetics
  • Calcium Channels, L-Type / genetics
  • Calcium-Binding Proteins*
  • DNA Mutational Analysis
  • Electrophysiology
  • Humans
  • In Vitro Techniques
  • Membrane Glycoproteins / genetics
  • Membrane Proteins / genetics
  • Microelectrodes
  • Microscopy, Electron
  • Myasthenic Syndromes, Congenital / classification
  • Myasthenic Syndromes, Congenital / genetics
  • Myasthenic Syndromes, Congenital / physiopathology*
  • Myasthenic Syndromes, Congenital / ultrastructure
  • Nerve Tissue Proteins / genetics
  • Neuromuscular Junction / drug effects
  • Neuromuscular Junction / genetics*
  • Neuromuscular Junction / physiopathology
  • Neuromuscular Junction / ultrastructure
  • Qa-SNARE Proteins
  • Sequence Alignment
  • Synapses / drug effects
  • Synapses / genetics
  • Synapses / physiology
  • Synapses / ultrastructure
  • Synaptic Transmission*
  • Synaptotagmins
  • Syntaxin 1


  • CACNA1A protein, human
  • CACNB2 protein, human
  • Calcium Channel Blockers
  • Calcium Channels
  • Calcium Channels, L-Type
  • Calcium-Binding Proteins
  • Membrane Glycoproteins
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Qa-SNARE Proteins
  • STX1A protein, human
  • Syntaxin 1
  • Synaptotagmins
  • Calcium