Ca2+ microdomains near plasma membrane Ca2+ channels: impact on cell function

Abstract

In eukaryotic cells, a rise in cytoplasmic Ca(2+) can activate a plethora of responses that operate on time scales ranging from milliseconds to days. Inherent to the use of a promiscuous signal like Ca(2+) is the problem of specificity: how can Ca(2+) activate some responses but not others? We now know that the spatial profile of the Ca(2+) signal is important Ca(2+) does not simply rise uniformly throughout the cytoplasm upon stimulation but can reach very high levels locally, creating spatial gradients. The most fundamental local Ca(2+) signal is the Ca(2+) microdomain that develops rapidly near open plasmalemmal Ca(2+) channels like voltage-gated L-type (Cav1.2) and store-operated CRAC channels. Recent work has revealed that Ca(2+) microdomains arising from these channels are remarkably versatile in triggering a range of responses that differ enormously in both temporal and spatial profile. Here, I delineate basic features of Ca(2+) microdomains and then describe how these highly local signals are used by Ca(2+)-permeable channels to drive cellular responses.

Figure 1. Amplitude and spatial extent of Ca²⁺ microdomains

A and B, plots of the numerically calculated profile of a Ca²⁺ microdomain near an open L-type Ca²⁺ channel (A) and a CRAC channel (B). Single channel currents were 0.144 pA (Church & Stanley, 1996) and 1.5 fA (Zweifach & Lewis, 1995), respectively. Endogenous Ca²⁺ buffering was ignored. C, the distance (λ) a Ca²⁺ ion diffuses before it is captured by some widely used Ca²⁺ chelators is shown and is stated next to each chelator. All concentrations are in mm. D, various properties of widely used fluorescent dyes (Lattanzio. & Bartschat (1991) and the calculated λ. All concentrations were 100 μm, corresponding to the levels used experimentally. For C and D, resting Ca²⁺ was set at 100 nm and the free chelator concentration then calculated. λ is not a precise calculation because buffer is not present in excess.

Figure 2. The cartoon summarizing the impact of Ca²⁺ microdomains near L-type (A) and CRAC (B) channels on cell function

CaM denotes calmodulin, 5LOX 5-lipoxygenase.