Buffer mobility and the regulation of neuronal calcium domains - PubMed (original) (raw)

Review

Buffer mobility and the regulation of neuronal calcium domains

Elizabeth A Matthews et al. Front Cell Neurosci. 2015.

Abstract

The diffusion of calcium inside neurons is determined in part by the intracellular calcium binding species that rapidly bind to free calcium ions upon entry. It has long been known that some portion of a neuron's intracellular calcium binding capacity must be fixed or poorly mobile, as calcium diffusion is strongly slowed in the intracellular environment relative to diffusion in cytosolic extract. The working assumption was that these immobile calcium binding sites are provided by structural proteins bound to the cytoskeleton or intracellular membranes and may thereby be relatively similar in composition and capacity across different cell types. However, recent evidence suggests that the immobile buffering capacity can vary greatly between cell types and that some mobile calcium binding proteins may alter their mobility upon binding calcium, thus blurring the line between mobile and immobile. The ways in which immobile buffering capacity might be relevant to different calcium domains within neurons has been explored primarily through modeling. In certain regimes, the presence of immobile buffers and the interaction between mobile and immobile buffers have been shown to result in complex spatiotemporal patterns of free calcium. In total, these experimental and modeling findings call for a more nuanced consideration of the local intracellular calcium microenvironment. In this review we focus on the different amounts, affinities, and mobilities of immobile calcium binding species; propose a new conceptual category of physically diffusible but functionally immobile buffers; and discuss how these buffers might interact with mobile calcium binding partners to generate characteristic calcium domains.

Keywords: calcium buffer; calcium domains; diffusion coefficient; immobile; mobile.

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Figures

FIGURE 1

FIGURE 1

Simulations were run using CalC (Matveev et al., 2004; http://web.njit.edu/\~matveev; Version 6.7.4). Resting calcium concentration was set at 100 nM. We simulate a calcium current of 0.2 pA through a generic calcium channel. Parameters for the immobile buffer were taken from the experimental results summarized in Table 1. (A) The presence of immobile buffer slows the arrival at steady state free calcium concentrations at all points in space surrounding a calcium source. The time of channel opening was increased to a non-physiological 10 ms so that the prolonged time course could be better illustrated. However, in the case of high immobile buffering capacity, steady state concentrations were clearly not reached even after 10 ms. In the case of a more physiologically relevant open time of 0.8 ms, the free calcium concentration is even further from reaching a steady state level and the slowing effect of immobile buffers is even more prominent (inset). A similar effect is seen after the channel closes. Calcium is gradually released from immobile buffers, prolonging the return to resting calcium concentrations. (B) The localizing effect of immobile buffers on microdomains during calcium entry was plotted for a 1 ms calcium channel opening. At all illustrated points in space, the immobile buffer reduces free calcium concentration; this localizing effect on peak free calcium concentration is known to be similar for a mobile buffer. (C) The collapse of a microdomain after the closing of a calcium channel is illustrated for conditions with no buffering (left), a low immobile buffer capacity (center) and a high immobile buffer capacity (right). The spatial calcium gradient is shown immediately before closing (0 ms), and at 0.2, 0.5, and 1.0 ms following channel closure. The strong prolongation of the free calcium domain by the immobile buffer is apparent. With a high immobile buffer capacity, the domain remains above 1 μM free calcium even 1 ms after the channel has closed. This effect is unique to immobile buffers; a mobile buffer will disperse the spatial gradient and speed the local return to resting levels. (D) To explore the diffusion limits at which a mobile buffer behaves as a functionally immobile buffer, the prolongation of a calcium microdomain was examined. A calcium source was opened for 1 ms, then the decay of the microdomain at 15 nm from the channel was plotted over time. The initial condition had an immobile buffer with a capacity of 15; under these conditions, the free calcium concentration remains elevated for several milliseconds. When the diffusion coefficient was ≤ 1 μm2/s, the lifetime was further increased by the mobile buffer. This indicates that the poorly mobile buffer functions as though it were physically immobile.

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