Neuroscience 2003 Abstract
| Presentation Number: | 766.6 |
|---|---|
| Abstract Title: | Molecular determinants of Ca<sup>2+</sup>- and calmodulin-dependent regulation of Ca<sub>V</sub>2.1. |
| Authors: |
Lee, A.*1
; Zhou, H.1
; Sun, H.1
; Scheuer, T.2
; Catterall, W. A.2
1Dept. of Pharmacol., Emory Univ., Atlanta, GA 2WA, 5123 Rollins Res. Bldg., 30322, |
| Primary Theme and Topics |
Synaptic Transmission and Excitability - Ion Channels -- Calcium channels |
| Session: |
766. Calcium Channels:Physiology & Pharmacology Slide |
| Presentation Time: | Wednesday, November 12, 2003 9:15 AM-9:15 AM |
| Location: | Morial Convention Center - Room 253 |
| Keywords: | synaptic plasticity, presynaptic, neuron, neuromodulation |
In the nervous system, Ca2+-dependent facilitation and inactivation (CDF and CDI) of Cav2.1 channels may fine-tune presynaptic Ca2+ concentrations and contribute to activity-dependent synaptic plasticity. The mechanism for this dual feedback regulation by Ca2+ may involve calmodulin (CaM) binding directly to two sites, a CaM-binding domain (CBD) and an IQ-like domain in the C-terminal portion of the Cav2.1 α1 subunit (α12.1). In this study, we describe the molecular determinants for Ca2+-dependent modulation of Cav2.1, which reside both in CaM itself and in the CBD and IQ-like domain of α12.1. In transfected tsA-201 cells, CDI but not CDF was largely reduced in channels lacking the CBD. By contrast, alanine substitution of the first two residues of the IQ-like domain (IQ-AA) prevented CDF but not CDI. Moreover, Cav2.1 channels lacking the CBD and containing the IQ-AA mutations were deficient in both CDI and CDF. Ca2+ binding to CaM was critical for CDI and CDF, which were both nearly abolished by inactivating mutations in all four Ca2+-binding EF-hand motifs of CaM. While CDF was impaired in Cav2.1 channels coexpressed with CaM mutants unable to bind Ca2+ either in the N- or C-terminal EF-hands (CaM1,2 or CaM3,4), CDI was selectively prevented by CaM1,2 but not CaM3,4. In binding assays, CaM1,2 and CaM3,4 were unable to bind the CBD. By contrast, the IQ-like domain retained binding to CaM3,4 but not to CaM1,2. These findings suggest that for Cav2.1 channels, conformational states favoring CDF and CDI are encoded by Ca2+ binding to particular lobes of CaM as well as unique molecular interactions of Ca2+/CaM with the CBD and IQ-like domain of α12.1.
Supported by NIH grants NS044922 to A.L. and NS22625 to W.A.C.
Sample Citation:
[Authors]. [Abstract Title]. Program No. XXX.XX. 2003 Neuroscience Meeting Planner. New Orleans, LA: Society for Neuroscience, 2003. Online.
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