Ca²⁺ regulation of constitutive vesicle trafficking

Constitutive vesicle trafficking is the default pathway used by all cells for movement of intracellular cargoes between subcellular compartments and in and out of the cell. Classically, constitutive trafficking was thought to be continuous and unregulated, in contrast to regulated secretion, wherein vesicles are stored intracellularly until undergoing synchronous membrane fusion following a Ca²⁺ signal. However, as shown in the literature reviewed here, many continuous trafficking steps can be up- or down-regulated by Ca²⁺, including several steps associated with human pathologies. Notably, we describe a series of Ca²⁺ pumps, channels, Ca²⁺-binding effector proteins, and their trafficking machinery targets that together regulate the flux of cargo in response to genetic alterations as well as baseline and agonist-dependent Ca²⁺ signals. Here, we review the most recent advances, organized by organellar location, that establish the importance of these components in trafficking steps. Ultimately, we conclude that Ca²⁺ regulates an expanding series of distinct mechanistic steps. Furthermore, the involvement of Ca²⁺ in trafficking is complex. For example, in some cases, the same Ca²⁺ effectors regulate surprisingly distinct trafficking steps, or even the same trafficking step with opposing influences, through binding to different target proteins.