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A "mix-and-match" approach to designing Ca(2+) microdomains at membrane-contact sites.

Penny CJ, Kilpatrick BS, Min Han J, Sneyd J, Patel S - Commun Integr Biol (2014)

Bottom Line: However, at present we know little of how Ca(2+) release events are coordinated at these experimentally intractable junctions.We therefore developed a computational model of lysosome-ER microdomains, which suggested that small leaks of Ca(2+) from the lysosome couple to Ca(2+)-sensitive Ins(1,4,5)P 3 receptors on the ER to generate global, microdomain-dependent Ca(2+) signals.Here we discuss how the "mix-and-match" arrangement of different Ca(2+) signaling proteins on the "source" and "target" membranes might generate functionally heterogeneous Ca(2+) microdomains.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell and Developmental Biology; University College London; London, UK.

ABSTRACT
Ca(2+) microdomains are critical for regulating cellular activity and often form at membrane contact sites. Such sites between lysosomes and the ER potentially provide a platform for signaling by the Ca(2+) mobilizing messenger NAADP. However, at present we know little of how Ca(2+) release events are coordinated at these experimentally intractable junctions. We therefore developed a computational model of lysosome-ER microdomains, which suggested that small leaks of Ca(2+) from the lysosome couple to Ca(2+)-sensitive Ins(1,4,5)P 3 receptors on the ER to generate global, microdomain-dependent Ca(2+) signals. Here we discuss how the "mix-and-match" arrangement of different Ca(2+) signaling proteins on the "source" and "target" membranes might generate functionally heterogeneous Ca(2+) microdomains.

No MeSH data available.


Figure 1. Heterogeneity of Ca2+ microdomains at membrane contact sites. MCS between the source (top) and target (bottom) membranes allow functional Ca2+ microdomains to form between them. Ca2+ influx through voltage gated Ca2+ channels (Cav) in the PM-SR MCS of the dyadic cleft (left) forms a high [Ca2+] microdomain (dark circle) to initiate Ca2+ release from low-affinity ryanodine receptors (RyR). Ca2+ release through inositol trisphosphate receptors (Ins(1,4,5)P3R) in ER-mitochondria MCS (center) also forms a high [Ca2+] microdomain to facilitate mitochondrial Ca2+ uptake by the low-affinity mitochondrial uniporter (MCU). Ca2+ release through 2-pore Channels (TPC) in lysosome-ER MCS (right) forms a low [Ca2+] microdomain (light circle) due to the presence of SERCA (S) but which is nevertheless able to activate high-affinity Ins(1,4,5)P3Rs.
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Figure 1: Figure 1. Heterogeneity of Ca2+ microdomains at membrane contact sites. MCS between the source (top) and target (bottom) membranes allow functional Ca2+ microdomains to form between them. Ca2+ influx through voltage gated Ca2+ channels (Cav) in the PM-SR MCS of the dyadic cleft (left) forms a high [Ca2+] microdomain (dark circle) to initiate Ca2+ release from low-affinity ryanodine receptors (RyR). Ca2+ release through inositol trisphosphate receptors (Ins(1,4,5)P3R) in ER-mitochondria MCS (center) also forms a high [Ca2+] microdomain to facilitate mitochondrial Ca2+ uptake by the low-affinity mitochondrial uniporter (MCU). Ca2+ release through 2-pore Channels (TPC) in lysosome-ER MCS (right) forms a low [Ca2+] microdomain (light circle) due to the presence of SERCA (S) but which is nevertheless able to activate high-affinity Ins(1,4,5)P3Rs.

Mentions: Computational models of Ca2+ dynamics often have a modular design, whereby individual models for each Ca2+ transport process are assembled together to generate an appropriate, relevant system. This rule is consistent at different levels of computational complexity.9,10,17 We suggest that viewing “real” microdomains in this modular fashion can aid our understanding of their architecture in live cells. As discussed, the variable expression of individual Ca2+ channels and pumps within MCS, on either the source or target membrane, can profoundly alter the properties of microdomains. This “mix-and-match” approach may account for the functionally diverse behaviors that microdomains coordinate. (Fig. 1)


A "mix-and-match" approach to designing Ca(2+) microdomains at membrane-contact sites.

Penny CJ, Kilpatrick BS, Min Han J, Sneyd J, Patel S - Commun Integr Biol (2014)

Figure 1. Heterogeneity of Ca2+ microdomains at membrane contact sites. MCS between the source (top) and target (bottom) membranes allow functional Ca2+ microdomains to form between them. Ca2+ influx through voltage gated Ca2+ channels (Cav) in the PM-SR MCS of the dyadic cleft (left) forms a high [Ca2+] microdomain (dark circle) to initiate Ca2+ release from low-affinity ryanodine receptors (RyR). Ca2+ release through inositol trisphosphate receptors (Ins(1,4,5)P3R) in ER-mitochondria MCS (center) also forms a high [Ca2+] microdomain to facilitate mitochondrial Ca2+ uptake by the low-affinity mitochondrial uniporter (MCU). Ca2+ release through 2-pore Channels (TPC) in lysosome-ER MCS (right) forms a low [Ca2+] microdomain (light circle) due to the presence of SERCA (S) but which is nevertheless able to activate high-affinity Ins(1,4,5)P3Rs.
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Figure 1: Figure 1. Heterogeneity of Ca2+ microdomains at membrane contact sites. MCS between the source (top) and target (bottom) membranes allow functional Ca2+ microdomains to form between them. Ca2+ influx through voltage gated Ca2+ channels (Cav) in the PM-SR MCS of the dyadic cleft (left) forms a high [Ca2+] microdomain (dark circle) to initiate Ca2+ release from low-affinity ryanodine receptors (RyR). Ca2+ release through inositol trisphosphate receptors (Ins(1,4,5)P3R) in ER-mitochondria MCS (center) also forms a high [Ca2+] microdomain to facilitate mitochondrial Ca2+ uptake by the low-affinity mitochondrial uniporter (MCU). Ca2+ release through 2-pore Channels (TPC) in lysosome-ER MCS (right) forms a low [Ca2+] microdomain (light circle) due to the presence of SERCA (S) but which is nevertheless able to activate high-affinity Ins(1,4,5)P3Rs.
Mentions: Computational models of Ca2+ dynamics often have a modular design, whereby individual models for each Ca2+ transport process are assembled together to generate an appropriate, relevant system. This rule is consistent at different levels of computational complexity.9,10,17 We suggest that viewing “real” microdomains in this modular fashion can aid our understanding of their architecture in live cells. As discussed, the variable expression of individual Ca2+ channels and pumps within MCS, on either the source or target membrane, can profoundly alter the properties of microdomains. This “mix-and-match” approach may account for the functionally diverse behaviors that microdomains coordinate. (Fig. 1)

Bottom Line: However, at present we know little of how Ca(2+) release events are coordinated at these experimentally intractable junctions.We therefore developed a computational model of lysosome-ER microdomains, which suggested that small leaks of Ca(2+) from the lysosome couple to Ca(2+)-sensitive Ins(1,4,5)P 3 receptors on the ER to generate global, microdomain-dependent Ca(2+) signals.Here we discuss how the "mix-and-match" arrangement of different Ca(2+) signaling proteins on the "source" and "target" membranes might generate functionally heterogeneous Ca(2+) microdomains.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell and Developmental Biology; University College London; London, UK.

ABSTRACT
Ca(2+) microdomains are critical for regulating cellular activity and often form at membrane contact sites. Such sites between lysosomes and the ER potentially provide a platform for signaling by the Ca(2+) mobilizing messenger NAADP. However, at present we know little of how Ca(2+) release events are coordinated at these experimentally intractable junctions. We therefore developed a computational model of lysosome-ER microdomains, which suggested that small leaks of Ca(2+) from the lysosome couple to Ca(2+)-sensitive Ins(1,4,5)P 3 receptors on the ER to generate global, microdomain-dependent Ca(2+) signals. Here we discuss how the "mix-and-match" arrangement of different Ca(2+) signaling proteins on the "source" and "target" membranes might generate functionally heterogeneous Ca(2+) microdomains.

No MeSH data available.