Lanthanide gadolinium (Gd3+) blocks CaV1.2 channels at the selectivity filter. Here we investigated whether Gd3+ block interferes with Ca2+-dependent inactivation, which requires Ca2+ entry through the same site. Using brief pulses to 200 mV that relieve Gd3+ block but not inactivation, we monitored how the proportions of open and open-blocked channels change during inactivation. We found that blocked channels inactivate much less. This is expected for Gd3+ block of the Ca2+ influx that enhances inactivation. However, we also found that the extent of Gd3+ block did not change when inactivation was reduced by abolition of Ca2+/calmodulin interaction, showing that Gd3+ does not block the inactivated channel. Thus, Gd3+ block and inactivation are mutually exclusive, suggesting action at a common site. These observations suggest that inactivation causes a change at the selectivity filter that either hides the Gd3+ site or reduces its affinity, or that Ca2+ occupies the binding site at the selectivity filter in inactivated channels. The latter possibility is supported by previous findings that the EEQE mutation of the selectivity EEEE locus is void of Ca2+-dependent inactivation (Zong Z.Q., J.Y. Zhou, and T. Tanabe. 1994. Biochem. Biophys. Res. Commun. 201:1117–11123), and that Ca2+-inactivated channels conduct Na+ when Ca2+ is removed from the extracellular medium (Babich O., D. Isaev, and R. Shirokov. 2005. J. Physiol. 565:709–717). Based on these results, we propose that inactivation increases affinity of the selectivity filter for Ca2+ so that Ca2+ ion blocks the pore. A minimal model, in which the inactivation “gate” is an increase in affinity of the selectivity filter for permeating ions, successfully simulates the characteristic U-shaped voltage dependence of inactivation in Ca2+.
Skip Nav Destination
Article navigation
1 June 2007
Article|
May 29 2007
Ca2+-dependent Inactivation of CaV1.2 Channels Prevents Gd3+ Block: Does Ca2+ Block the Pore of Inactivated Channels?
Olga Babich,
Olga Babich
1Department of Pharmacology and Physiology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103
Search for other works by this author on:
Victor Matveev,
Victor Matveev
2Department of Mathematical Sciences, New Jersey Institute of Technology, Newark, NJ 07102
Search for other works by this author on:
Andrew L. Harris,
Andrew L. Harris
1Department of Pharmacology and Physiology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103
Search for other works by this author on:
Roman Shirokov
Roman Shirokov
1Department of Pharmacology and Physiology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103
Search for other works by this author on:
Olga Babich
1Department of Pharmacology and Physiology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103
Victor Matveev
2Department of Mathematical Sciences, New Jersey Institute of Technology, Newark, NJ 07102
Andrew L. Harris
1Department of Pharmacology and Physiology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103
Roman Shirokov
1Department of Pharmacology and Physiology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103
Correspondence to Roman Shirokov: [email protected]
O. Babich's present address is Molecular Pharmacology Department, AstraZeneca R&D, Södertälje, Sweden.
Received:
January 03 2007
Accepted:
April 20 2007
Online ISSN: 1540-7748
Print ISSN: 0022-1295
The Rockefeller University Press
2007
J Gen Physiol (2007) 129 (6): 477–483.
Article history
Received:
January 03 2007
Accepted:
April 20 2007
Connected Content
Citation
Olga Babich, Victor Matveev, Andrew L. Harris, Roman Shirokov; Ca2+-dependent Inactivation of CaV1.2 Channels Prevents Gd3+ Block: Does Ca2+ Block the Pore of Inactivated Channels? . J Gen Physiol 1 June 2007; 129 (6): 477–483. doi: https://doi.org/10.1085/jgp.200709734
Download citation file:
Sign in
Don't already have an account? Register
Client Account
You could not be signed in. Please check your email address / username and password and try again.
Could not validate captcha. Please try again.
Sign in via your Institution
Sign in via your InstitutionSuggested Content
Block of CaV1.2 Channels by Gd3+ Reveals Preopening Transitions in the Selectivity Filter
J Gen Physiol (May,2007)
Blockade of current through single calcium channels by trivalent lanthanide cations. Effect of ionic radius on the rates of ion entry and exit.
J Gen Physiol (April,1990)
Modulation of the Voltage Sensor of L-type Ca2+ Channels by Intracellular Ca2+
J Gen Physiol (April,2004)
Email alerts
Advertisement