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Molecular determinants of inactivation in voltage-gated Ca2+ channels
S Hering1, S Berjukow, S Sokolov
1Institut für Biochemische Pharmakologie, Peter-Mayr-Strasse 1, A-6020 Innsbruck, Austria. steffen.hering@uibk.ac.at
Abstract:
Evolution has created a large family of different classes of voltage-gated Ca2+ channels and a variety of additional splice variants with different inactivation properties. Inactivation controls the amount of Ca2+ entry during an action potential and is, therefore, believed to play an important role in tissue-specific Ca2+ signalling. Furthermore, mutations in a neuronal Ca2+ channel (Ca(v)2.1) that are associated with the aetiology of neurological disorders such as familial hemiplegic migraine and ataxia cause significant changes in the process of channel inactivation. Ca2+ channels of a given subtype may inactivate by three different conformational changes: a fast and a slow voltage-dependent inactivation process and in some channel types by an additional Ca2+-dependent inactivation mechanism. Inactivation kinetics of Ca2+ channels are determined by the intrinsic properties of their pore-forming alpha1-subunits and by interactions with other channel subunits. This review focuses on structural determinants of Ca2+ channel inactivation in different parts of Ca2+ channel alpha1-subunits, including pore-forming transmembrane segments and loops, intracellular domain linkers and the carboxyl terminus. Inactivation is also affected by the interaction of the alpha1-subunits with auxiliary beta-subunits and intracellular regulator proteins. The evidence shows that pore-forming S6 segments and conformational changes in extra- (pore loop) and intracellular linkers connected to pore-forming segments may play a principal role in the modulation of Ca2+ channel inactivation. Structural concepts of Ca2+ channel inactivation are discussed.
Insights
Voltage-gated calcium channels (Ca2+) have evolved diverse inactivation properties crucial for cell signaling. Structural elements within alpha1-subunits and auxiliary proteins significantly influence these inactivation mechanisms.
Area of Science:
- Molecular biology
- Neuroscience
- Biophysics
Background:
- Voltage-gated calcium channels (Ca2+) exhibit diverse classes and splice variants with distinct inactivation properties.
- Inactivation of Ca2+ channels regulates Ca2+ influx during action potentials, impacting tissue-specific signaling.
- Mutations in neuronal Ca(v)2.1 channels linked to neurological disorders alter inactivation processes.
Purpose of the Study:
- To review the structural determinants of Ca2+ channel inactivation.
- To elucidate the roles of different channel domains and subunit interactions in modulating inactivation kinetics.
- To discuss structural concepts governing Ca2+ channel inactivation.
Main Methods:
- Literature review of studies on voltage-gated Ca2+ channel structure and function.
- Analysis of research on inactivation mechanisms, including voltage-dependent and Ca2+-dependent processes.
- Focus on structural components like alpha1-subunits, pore loops, transmembrane segments, and auxiliary subunits.
Main Results:
- Ca2+ channel inactivation involves fast and slow voltage-dependent processes, and in some cases, Ca2+-dependent mechanisms.
- Inactivation kinetics are determined by intrinsic properties of alpha1-subunits and interactions with other subunits.
- Pore-forming S6 segments, pore loops, and intracellular linkers are key structural determinants of inactivation modulation.
Conclusions:
- Structural features of alpha1-subunits, particularly pore-associated regions and intracellular linkers, are principal modulators of Ca2+ channel inactivation.
- Interactions with auxiliary beta-subunits and regulator proteins further influence inactivation.
- Understanding these structural determinants is crucial for comprehending Ca2+ channel function and dysfunction in neurological disorders.