Ca2+ regulation of constitutive vesicle trafficking

Abstract

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.

Keywords: Golgi; apoptosis-linked gene 2 (ALG-2); calcium; calcium channel; calcium signaling; endoplasmic reticulum; late endosomes; lysosomes; secretion; vesicle coat; vesicle trafficking.

Figure 1.. Ca²⁺ concentrations in constitutive trafficking.

Of the Ca²⁺ pools depicted, the low end is the cytosol, with a free [Ca²⁺] of about 100 nM. The concentration of Ca²⁺ decreases from the endoplasmic reticulum (ER) (~500 µM) to the cis-Golgi (~300 µM) to the trans-Golgi network (TGN) (50–100 µM)^,, in the same direction as anterograde secretion. Lysosomes contain a similar [Ca²⁺] to the ER^,. At the high end is the extracellular space with typical [Ca²⁺] of 1.2 to 1.5 mM. PM, plasma membrane; VTC, vesicular tubular cluster.

Figure 2.. Ca²⁺ regulation of constitutive secretion at the endoplasmic reticulum.

Prominent examples from the text are depicted and color-coded at an example endoplasmic reticulum exit site (ERES). Greens: trafficking machinery; pinks/purples: Ca²⁺-binding proteins; blues: Ca²⁺ pumps or channels; oranges: accessory proteins or cargo. Ub, monoubiquitination.

Figure 3.. Ca²⁺ regulation of constitutive secretion through the Golgi and trans-Golgi network (TGN).

Prominent examples from the text are depicted and color-coded in various Golgi compartments. Greens: trafficking machinery; pinks/purples: Ca²⁺-binding proteins; blues: Ca²⁺ pumps or channels; oranges: accessory proteins or cargo. P, phosphorylation.

Figure 4.. Ca²⁺ regulation of constitutive secretion at the lysosome.

Prominent examples from the text are depicted and color-coded. Greens: trafficking machinery; pinks/purples: Ca²⁺-binding proteins; blues: Ca²⁺ pumps or channels; oranges: accessory proteins or cargo.