Limits...
Analyzing and Quantifying the Gain-of-Function Enhancement of IP3 Receptor Gating by Familial Alzheimer's Disease-Causing Mutants in Presenilins.

Mak DO, Cheung KH, Toglia P, Foskett JK, Ullah G - PLoS Comput. Biol. (2015)

Bottom Line: We found that in addition to the high occupancy of the high-activity (H) mode and the low occupancy of the low-activity (L) mode, IP3R in FAD-causing mutant PS-expressing cells exhibits significantly longer mean life-time for the H mode and shorter life-time for the L mode, leading to shorter mean close-time and hence high open probability of the channel in comparison to IP3R in cells expressing wild-type PS.The model is then used to extrapolate the behavior of the channel to a wide range of IP3 and Ca(2+) concentrations and quantify the sensitivity of IP3R to its two ligands.We further demonstrate with simulations that the relatively longer time spent by IP3R in the H mode leads to the observed higher frequency of local Ca(2+) signals, which can account for the more frequent global Ca(2+) signals observed, while the enhanced activity of the channel at extremely low ligand concentrations will lead to spontaneous Ca(2+) signals in cells expressing FAD-causing mutant PS.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

ABSTRACT
Familial Alzheimer's disease (FAD)-causing mutant presenilins (PS) interact with inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) Ca(2+) release channels resulting in enhanced IP3R channel gating in an amyloid beta (Aβ) production-independent manner. This gain-of-function enhancement of IP3R activity is considered to be the main reason behind the upregulation of intracellular Ca(2+) signaling in the presence of optimal and suboptimal stimuli and spontaneous Ca(2+) signals observed in cells expressing mutant PS. In this paper, we employed computational modeling of single IP3R channel activity records obtained under optimal Ca(2+) and multiple IP3 concentrations to gain deeper insights into the enhancement of IP3R function. We found that in addition to the high occupancy of the high-activity (H) mode and the low occupancy of the low-activity (L) mode, IP3R in FAD-causing mutant PS-expressing cells exhibits significantly longer mean life-time for the H mode and shorter life-time for the L mode, leading to shorter mean close-time and hence high open probability of the channel in comparison to IP3R in cells expressing wild-type PS. The model is then used to extrapolate the behavior of the channel to a wide range of IP3 and Ca(2+) concentrations and quantify the sensitivity of IP3R to its two ligands. We show that the gain-of-function enhancement is sensitive to both IP3 and Ca(2+) and that very small amount of IP3 is required to stimulate IP3R channels in the presence of FAD-causing mutant PS to the same level of activity as channels in control cells stimulated by significantly higher IP3 concentrations. We further demonstrate with simulations that the relatively longer time spent by IP3R in the H mode leads to the observed higher frequency of local Ca(2+) signals, which can account for the more frequent global Ca(2+) signals observed, while the enhanced activity of the channel at extremely low ligand concentrations will lead to spontaneous Ca(2+) signals in cells expressing FAD-causing mutant PS.

No MeSH data available.


Related in: MedlinePlus

Mean gating properties of IP3R in the presence of PS1-WT and PS1-M146L.Experimental values are shown by symbols (filled symbols for data that are used to derive the parameters for our model, open symbols for data not used for parameter derivation), theoretical values calculated from the twelve-state model using corresponding parameters are shown by lines. Mean Po (A), τc (B), and τo (C) of IP3RPS1WT (solid lines and squares) and IP3RPS1M146L (dashed lines and circles) at 𝓘 = 33nM, 100nM, and 10μM (in turquoise, blue, and magenta, respectively) as functions of 𝓒. Data for 𝓘 = 100nM (blue symbols) were published in [15], and data for 𝓘 = 33 nM and 10 uM (turquoise and magenta symbols, respectively) were published in [14]. (C) Because experimental τo values did not show any strong systematic trend as 𝓘 varied (from 33 nM through 100 nM to 10 μM), theoretical values of τo generated by the models for all 𝓘 (33nM, 100 nM or 10 μM) are the same (shown in black, solid line for IP3RPS1WT and dashed line for IP3RPS1M146L). Prevalences (D) and life-times (E) of the three gating modes (red, orange, and green for L, I, and H modes, respectively) of IP3RPS1WT (solid lines and squares) and IP3RPS1M146L (dashed lines and circles) as a function of 𝓒 at 𝓘 = 100nM. In (D), the open triangles are data for IP3RnoPS1 at saturating 𝓘 = 10μM [21] showing that modal prevalences of IP3RPS1M146L at 𝓘 = 100 nM are similar to those of IP3RnoPS1 at 𝓘 = 10μM. Error bars represent standard error of the mean.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4595473&req=5

pcbi.1004529.g003: Mean gating properties of IP3R in the presence of PS1-WT and PS1-M146L.Experimental values are shown by symbols (filled symbols for data that are used to derive the parameters for our model, open symbols for data not used for parameter derivation), theoretical values calculated from the twelve-state model using corresponding parameters are shown by lines. Mean Po (A), τc (B), and τo (C) of IP3RPS1WT (solid lines and squares) and IP3RPS1M146L (dashed lines and circles) at 𝓘 = 33nM, 100nM, and 10μM (in turquoise, blue, and magenta, respectively) as functions of 𝓒. Data for 𝓘 = 100nM (blue symbols) were published in [15], and data for 𝓘 = 33 nM and 10 uM (turquoise and magenta symbols, respectively) were published in [14]. (C) Because experimental τo values did not show any strong systematic trend as 𝓘 varied (from 33 nM through 100 nM to 10 μM), theoretical values of τo generated by the models for all 𝓘 (33nM, 100 nM or 10 μM) are the same (shown in black, solid line for IP3RPS1WT and dashed line for IP3RPS1M146L). Prevalences (D) and life-times (E) of the three gating modes (red, orange, and green for L, I, and H modes, respectively) of IP3RPS1WT (solid lines and squares) and IP3RPS1M146L (dashed lines and circles) as a function of 𝓒 at 𝓘 = 100nM. In (D), the open triangles are data for IP3RnoPS1 at saturating 𝓘 = 10μM [21] showing that modal prevalences of IP3RPS1M146L at 𝓘 = 100 nM are similar to those of IP3RnoPS1 at 𝓘 = 10μM. Error bars represent standard error of the mean.

Mentions: Representative time-series traces of the gating behavior of IP3RPS1WT and IP3RPS1M146L are shown in Fig 2A. Occupancy parameters for the twelve states in the model obtained by fitting the Po (Figs 2B, 3A) and prevalence (Fig 2C) data from IP3RPS1WT and IP3RPS1M146L are given in Table 1. Notice that some of the parameters for IP3RPS1WT are different from those in [22] because IP3RPS1WT behaves somewhat differently from the IP3R channel in wild type untransfected Sf9 cells (IP3RnoPS1), despite the general similarity in the gating of the two (Fig 3A–3C, triangles for IP3RnoPS1, squares and solid lines for IP3RPS1WT), especially Po at 𝓘 = 100nM and 400 nM < 𝓒 ≤ 1μM. It is remarkable that the occupancy of only 4 states changes in the presence of PS1-M146L as compared to PS1-WT. The four states are , and whose occupancies change by a factor of 4.587, 1.284, 1.718, and 0.018 respectively. Thus IP3RPS1M146L spends relatively more time in the states , and and less time in as compared to IP3RPS1WT. This is consistent with the prevalence data where there is a significant increase in πH (0.345 vs 0.836) at the cost of πL (0.515 vs 0.059) in IP3RPS1M146L as compared to IP3RPS1WT. πI on the other hand does not change significantly (0.14 vs 0.104) (Fig 2C). Thus the increase in Po is mainly due to the significantly less time spent by IP3RPS1M146L in and more time spent in (Fig 2B) as compared to IP3RPS1WT.


Analyzing and Quantifying the Gain-of-Function Enhancement of IP3 Receptor Gating by Familial Alzheimer's Disease-Causing Mutants in Presenilins.

Mak DO, Cheung KH, Toglia P, Foskett JK, Ullah G - PLoS Comput. Biol. (2015)

Mean gating properties of IP3R in the presence of PS1-WT and PS1-M146L.Experimental values are shown by symbols (filled symbols for data that are used to derive the parameters for our model, open symbols for data not used for parameter derivation), theoretical values calculated from the twelve-state model using corresponding parameters are shown by lines. Mean Po (A), τc (B), and τo (C) of IP3RPS1WT (solid lines and squares) and IP3RPS1M146L (dashed lines and circles) at 𝓘 = 33nM, 100nM, and 10μM (in turquoise, blue, and magenta, respectively) as functions of 𝓒. Data for 𝓘 = 100nM (blue symbols) were published in [15], and data for 𝓘 = 33 nM and 10 uM (turquoise and magenta symbols, respectively) were published in [14]. (C) Because experimental τo values did not show any strong systematic trend as 𝓘 varied (from 33 nM through 100 nM to 10 μM), theoretical values of τo generated by the models for all 𝓘 (33nM, 100 nM or 10 μM) are the same (shown in black, solid line for IP3RPS1WT and dashed line for IP3RPS1M146L). Prevalences (D) and life-times (E) of the three gating modes (red, orange, and green for L, I, and H modes, respectively) of IP3RPS1WT (solid lines and squares) and IP3RPS1M146L (dashed lines and circles) as a function of 𝓒 at 𝓘 = 100nM. In (D), the open triangles are data for IP3RnoPS1 at saturating 𝓘 = 10μM [21] showing that modal prevalences of IP3RPS1M146L at 𝓘 = 100 nM are similar to those of IP3RnoPS1 at 𝓘 = 10μM. Error bars represent standard error of the mean.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4595473&req=5

pcbi.1004529.g003: Mean gating properties of IP3R in the presence of PS1-WT and PS1-M146L.Experimental values are shown by symbols (filled symbols for data that are used to derive the parameters for our model, open symbols for data not used for parameter derivation), theoretical values calculated from the twelve-state model using corresponding parameters are shown by lines. Mean Po (A), τc (B), and τo (C) of IP3RPS1WT (solid lines and squares) and IP3RPS1M146L (dashed lines and circles) at 𝓘 = 33nM, 100nM, and 10μM (in turquoise, blue, and magenta, respectively) as functions of 𝓒. Data for 𝓘 = 100nM (blue symbols) were published in [15], and data for 𝓘 = 33 nM and 10 uM (turquoise and magenta symbols, respectively) were published in [14]. (C) Because experimental τo values did not show any strong systematic trend as 𝓘 varied (from 33 nM through 100 nM to 10 μM), theoretical values of τo generated by the models for all 𝓘 (33nM, 100 nM or 10 μM) are the same (shown in black, solid line for IP3RPS1WT and dashed line for IP3RPS1M146L). Prevalences (D) and life-times (E) of the three gating modes (red, orange, and green for L, I, and H modes, respectively) of IP3RPS1WT (solid lines and squares) and IP3RPS1M146L (dashed lines and circles) as a function of 𝓒 at 𝓘 = 100nM. In (D), the open triangles are data for IP3RnoPS1 at saturating 𝓘 = 10μM [21] showing that modal prevalences of IP3RPS1M146L at 𝓘 = 100 nM are similar to those of IP3RnoPS1 at 𝓘 = 10μM. Error bars represent standard error of the mean.
Mentions: Representative time-series traces of the gating behavior of IP3RPS1WT and IP3RPS1M146L are shown in Fig 2A. Occupancy parameters for the twelve states in the model obtained by fitting the Po (Figs 2B, 3A) and prevalence (Fig 2C) data from IP3RPS1WT and IP3RPS1M146L are given in Table 1. Notice that some of the parameters for IP3RPS1WT are different from those in [22] because IP3RPS1WT behaves somewhat differently from the IP3R channel in wild type untransfected Sf9 cells (IP3RnoPS1), despite the general similarity in the gating of the two (Fig 3A–3C, triangles for IP3RnoPS1, squares and solid lines for IP3RPS1WT), especially Po at 𝓘 = 100nM and 400 nM < 𝓒 ≤ 1μM. It is remarkable that the occupancy of only 4 states changes in the presence of PS1-M146L as compared to PS1-WT. The four states are , and whose occupancies change by a factor of 4.587, 1.284, 1.718, and 0.018 respectively. Thus IP3RPS1M146L spends relatively more time in the states , and and less time in as compared to IP3RPS1WT. This is consistent with the prevalence data where there is a significant increase in πH (0.345 vs 0.836) at the cost of πL (0.515 vs 0.059) in IP3RPS1M146L as compared to IP3RPS1WT. πI on the other hand does not change significantly (0.14 vs 0.104) (Fig 2C). Thus the increase in Po is mainly due to the significantly less time spent by IP3RPS1M146L in and more time spent in (Fig 2B) as compared to IP3RPS1WT.

Bottom Line: We found that in addition to the high occupancy of the high-activity (H) mode and the low occupancy of the low-activity (L) mode, IP3R in FAD-causing mutant PS-expressing cells exhibits significantly longer mean life-time for the H mode and shorter life-time for the L mode, leading to shorter mean close-time and hence high open probability of the channel in comparison to IP3R in cells expressing wild-type PS.The model is then used to extrapolate the behavior of the channel to a wide range of IP3 and Ca(2+) concentrations and quantify the sensitivity of IP3R to its two ligands.We further demonstrate with simulations that the relatively longer time spent by IP3R in the H mode leads to the observed higher frequency of local Ca(2+) signals, which can account for the more frequent global Ca(2+) signals observed, while the enhanced activity of the channel at extremely low ligand concentrations will lead to spontaneous Ca(2+) signals in cells expressing FAD-causing mutant PS.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

ABSTRACT
Familial Alzheimer's disease (FAD)-causing mutant presenilins (PS) interact with inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) Ca(2+) release channels resulting in enhanced IP3R channel gating in an amyloid beta (Aβ) production-independent manner. This gain-of-function enhancement of IP3R activity is considered to be the main reason behind the upregulation of intracellular Ca(2+) signaling in the presence of optimal and suboptimal stimuli and spontaneous Ca(2+) signals observed in cells expressing mutant PS. In this paper, we employed computational modeling of single IP3R channel activity records obtained under optimal Ca(2+) and multiple IP3 concentrations to gain deeper insights into the enhancement of IP3R function. We found that in addition to the high occupancy of the high-activity (H) mode and the low occupancy of the low-activity (L) mode, IP3R in FAD-causing mutant PS-expressing cells exhibits significantly longer mean life-time for the H mode and shorter life-time for the L mode, leading to shorter mean close-time and hence high open probability of the channel in comparison to IP3R in cells expressing wild-type PS. The model is then used to extrapolate the behavior of the channel to a wide range of IP3 and Ca(2+) concentrations and quantify the sensitivity of IP3R to its two ligands. We show that the gain-of-function enhancement is sensitive to both IP3 and Ca(2+) and that very small amount of IP3 is required to stimulate IP3R channels in the presence of FAD-causing mutant PS to the same level of activity as channels in control cells stimulated by significantly higher IP3 concentrations. We further demonstrate with simulations that the relatively longer time spent by IP3R in the H mode leads to the observed higher frequency of local Ca(2+) signals, which can account for the more frequent global Ca(2+) signals observed, while the enhanced activity of the channel at extremely low ligand concentrations will lead to spontaneous Ca(2+) signals in cells expressing FAD-causing mutant PS.

No MeSH data available.


Related in: MedlinePlus