Universität zu Köln

Beqollari, D., Romberg, C. F., Meza, U., Papadopoulos, S. and Bannister, R. A. (2014). Differential Effects of RGK Proteins on L-Type Channel Function in Adult Mouse Skeletal Muscle. Biophys. J., 106 (9). S. 1950 - 1958. CAMBRIDGE: CELL PRESS. ISSN 1542-0086

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Abstract

Work in heterologous systems has revealed that members of the Rad, Rem, Rem2, Gem/Kir (RGK) family of small SIP-binding proteins profoundly inhibit L-type Ca2+ channels via three mechanisms: 1), reduction of membrane expression; 2), immobilization of the voltage-sensors; and 3), reduction of P-o without impaired voltage-sensor movement. However, the question of which mode is the critical one for inhibition of L-type channels in their native environments persists. To address this conundrum in skeletal muscle, we overexpressed Rad and Rem in flexor digitorum brevis (FDB) fibers via in vivo electroporation and examined the abilities of these two RGK isoforms to modulate the L-type Ca2+ channel (Ca(V)1.1). We found that Rad and Rem both potently inhibit L-type current in FDB fibers. However, intramembrane charge movement was only reduced in fibers transfected with Rad; charge movement for Rem-expressing fibers was virtually identical to charge movement observed in naive fibers. This result indicated that Rem supports inhibition solely through a mechanism that allows for translocation or Ca(V)1.1's voltage-sensors, whereas Rad utilizes at least one mode that limits, voltage-sensor movement. Because Rad and Rem differ significantly only in their amino-termini, we constructed Rad-Rem. chimeras to probe the structural basis for the distinct specificities of Rad- and Rem-mediated inhibition. Using this approach, a chimera composed of the amino-terminus of Rem and the core/carboxyl-terminus of Rad inhibited L-type current without reducing charge movement. Conversely, a chimera having the amino-terminus of Rad fused to the core/carboxyl-terminus of. Rem inhibited L-type current with a concurrent reduction in charge movement. Thus, we have identified the amino-termini of Rad and Rem as the structural elements dictating the specific modes of inhibition of Ca(V)1.1.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Beqollari, D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Romberg, C. F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Meza, U. UNSPECIFIED UNSPECIFIED UNSPECIFIED Papadopoulos, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bannister, R. A. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-438525
DOI:	10.1016/j.bpj.2014.03.033
Journal or Publication Title:	Biophys. J.
Volume:	106
Number:	9
Page Range:	S. 1950 - 1958
Date:	2014
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	1542-0086
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SLOW CALCIUM CURRENT; CA(V)1.2 CHANNELS; CA2+ CHANNELS; REM; RAD; CALMODULIN; EXPRESSION; BINDING; MEMBER; LOCALIZATION Multiple languages Biophysics Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/43852