HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Functional consequences of mutations in the human alpha1A calcium channel subunit linked to familial hemiplegic migraine.

Abstract
Mutations in alpha1A, the pore-forming subunit of P/Q-type calcium channels, are linked to several human diseases, including familial hemiplegic migraine (FHM). We introduced the four missense mutations linked to FHM into human alpha1A-2 subunits and investigated their functional consequences after expression in human embryonic kidney 293 cells. By combining single-channel and whole-cell patch-clamp recordings, we show that all four mutations affect both the biophysical properties and the density of functional channels. Mutation R192Q in the S4 segment of domain I increased the density of functional P/Q-type channels and their open probability. Mutation T666M in the pore loop of domain II decreased both the density of functional channels and their unitary conductance (from 20 to 11 pS). Mutations V714A and I1815L in the S6 segments of domains II and IV shifted the voltage range of activation toward more negative voltages, increased both the open probability and the rate of recovery from inactivation, and decreased the density of functional channels. Mutation V714A decreased the single-channel conductance to 16 pS. Strikingly, the reduction in single-channel conductance induced by mutations T666M and V714A was not observed in some patches or periods of activity, suggesting that the abnormal channel may switch on and off, perhaps depending on some unknown factor. Our data show that the FHM mutations can lead to both gain- and loss-of-function of human P/Q-type calcium channels.
AuthorsM Hans, S Luvisetto, M E Williams, M Spagnolo, A Urrutia, A Tottene, P F Brust, E C Johnson, M M Harpold, K A Stauderman, D Pietrobon
JournalThe Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 19 Issue 5 Pg. 1610-9 (Mar 01 1999) ISSN: 0270-6474 [Print] United States
PMID10024348 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • CACNA1A protein, human
  • Calcium Channels
  • Calcium Channels, N-Type
  • Nerve Tissue Proteins
  • Recombinant Proteins
  • voltage-dependent calcium channel (P-Q type)
  • Calcium
Topics
  • Amino Acid Substitution
  • Calcium (metabolism)
  • Calcium Channels (genetics, metabolism)
  • Calcium Channels, N-Type
  • Cell Line
  • Cell Membrane Permeability (genetics)
  • Hemiplegia (genetics, physiopathology)
  • Humans
  • In Vitro Techniques
  • Ion Channel Gating (genetics, physiology)
  • Migraine Disorders (genetics, physiopathology)
  • Mutagenesis, Site-Directed
  • Mutation
  • Nerve Tissue Proteins (genetics, metabolism)
  • Patch-Clamp Techniques
  • Recombinant Proteins (metabolism)
  • Transfection

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: