Abstract
Neuronal voltage-gated Ca2+ (CaV) channels play a critical role in cellular excitability, synaptic transmission, excitation–transcription coupling and activation of intracellular signaling pathways. CaV channels are multiprotein complexes and their functional expression in the plasma membrane involves finely tuned mechanisms, including forward trafficking from the endoplasmic reticulum (ER) to the plasma membrane, endocytosis and recycling. Whether genetic or acquired, alterations and defects in the trafficking of neuronal CaV channels can have severe physiological consequences. In this review, we address the current evidence concerning the regulatory mechanisms which underlie precise control of neuronal CaV channel trafficking and we discuss their potential as therapeutic targets.
Highlights
Calcium (Ca2+) channels mediate numerous important physiological processes, and are abundant in many types of cells [1,2]
voltage-gated Ca2+ (CaV) channels are activated by membrane depolarization and they can be classified into two major categories: high-voltage-activated channels (HVAs), consisting of L-type (CaV1.1, 1.2, 1.3 and 1.4), P/Q-type (CaV2.1), N-type (CaV2.2), and R-type (CaV2.3) channels, and low-voltage-activated channels (LVAs), which encompass the T-type channels (CaV3.1, CaV3.2, CaV3.3) [3,4]
As we will discuss in the Endocytosis section of this review, G protein-coupled receptors (GPCRs) are potent modulators of CaV channel trafficking to the plasma membrane through direct interaction with the CaVα1 pore-forming subunit
Summary
Calcium (Ca2+) channels mediate numerous important physiological processes, and are abundant in many types of cells [1,2]. Discrepencies have been reported regarding the magnitude of the effect of mutating N1466 and N192 on CaV3.2 functional expression, it appears that these glycosylation sites are critical for the trafficking of the channels to the plasma membrane and that they affect the biophysical properties of the channels [44,45,46].
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