A stochastic model of ion channel cluster formation in the plasma membrane

Daisuke Sato, Gonzalo Hernández-Hernández, Collin Matsumoto, Sendoa Tajada, Claudia M. Moreno, Rose E. Dixon, Samantha O'Dwyer, Manuel F. Navedo, James S. Trimmer, Colleen E. Clancy, Marc D. Binder, L. Fernando Santana

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Ion channels are often found arranged into dense clusters in the plasma membranes of excitable cells, but the mechanisms underlying the formation and maintenance of these functional aggregates are unknown. Here, we tested the hypothesis that channel clustering is the consequence of a stochastic self-assembly process and propose a model by which channel clusters are formed and regulated in size. Our hypothesis is based on statistical analyses of the size distributions of the channel clusters we measured in neurons, ventricular myocytes, arterial smooth muscle, and heterologous cells, which in all cases were described by exponential functions, indicative of a Poisson process (i.e., clusters form in a continuous, independent, and memory-less fashion). We were able to reproduce the observed cluster distributions of five different types of channels in the membrane of excitable and tsA-201 cells in simulations using a computer model in which channels are "delivered" to the membrane at randomly assigned locations. The model's three parameters represent channel cluster nucleation, growth, and removal probabilities, the values of which were estimated based on our experimental measurements. We also determined the time course of cluster formation and membrane dwell time for CaV1.2 and TRPV4 channels expressed in tsA-201 cells to constrain our model. In addition, we elaborated a more complex version of our model that incorporated a self-regulating feedback mechanism to shape channel cluster formation. The strong inference we make from our results is that CaV1.2, CaV1.3, BK, and TRPV4 proteins are all randomly inserted into the plasma membranes of excitable cells and that they form homogeneous clusters that increase in size until they reach a steady state. Further, it appears likely that cluster size for a diverse set of membrane-bound proteins and a wide range of cell types is regulated by a common feedback mechanism.

Original languageEnglish (US)
Pages (from-to)1116-1134
Number of pages19
JournalThe Journal of general physiology
Volume151
Issue number9
DOIs
StatePublished - Sep 2 2019

Fingerprint

Ion Channels
Cell Membrane
Membranes
Computer Simulation
Muscle Cells
Smooth Muscle Myocytes
Cluster Analysis
Membrane Proteins
Maintenance
Neurons
Growth
Proteins

ASJC Scopus subject areas

  • Physiology

Cite this

A stochastic model of ion channel cluster formation in the plasma membrane. / Sato, Daisuke; Hernández-Hernández, Gonzalo; Matsumoto, Collin; Tajada, Sendoa; Moreno, Claudia M.; Dixon, Rose E.; O'Dwyer, Samantha; Navedo, Manuel F.; Trimmer, James S.; Clancy, Colleen E.; Binder, Marc D.; Santana, L. Fernando.

In: The Journal of general physiology, Vol. 151, No. 9, 02.09.2019, p. 1116-1134.

Research output: Contribution to journalArticle

Sato, D, Hernández-Hernández, G, Matsumoto, C, Tajada, S, Moreno, CM, Dixon, RE, O'Dwyer, S, Navedo, MF, Trimmer, JS, Clancy, CE, Binder, MD & Santana, LF 2019, 'A stochastic model of ion channel cluster formation in the plasma membrane', The Journal of general physiology, vol. 151, no. 9, pp. 1116-1134. https://doi.org/10.1085/jgp.201912327
Sato, Daisuke ; Hernández-Hernández, Gonzalo ; Matsumoto, Collin ; Tajada, Sendoa ; Moreno, Claudia M. ; Dixon, Rose E. ; O'Dwyer, Samantha ; Navedo, Manuel F. ; Trimmer, James S. ; Clancy, Colleen E. ; Binder, Marc D. ; Santana, L. Fernando. / A stochastic model of ion channel cluster formation in the plasma membrane. In: The Journal of general physiology. 2019 ; Vol. 151, No. 9. pp. 1116-1134.
@article{358e03d96d4b4f1da935914dc9b3cb54,
title = "A stochastic model of ion channel cluster formation in the plasma membrane",
abstract = "Ion channels are often found arranged into dense clusters in the plasma membranes of excitable cells, but the mechanisms underlying the formation and maintenance of these functional aggregates are unknown. Here, we tested the hypothesis that channel clustering is the consequence of a stochastic self-assembly process and propose a model by which channel clusters are formed and regulated in size. Our hypothesis is based on statistical analyses of the size distributions of the channel clusters we measured in neurons, ventricular myocytes, arterial smooth muscle, and heterologous cells, which in all cases were described by exponential functions, indicative of a Poisson process (i.e., clusters form in a continuous, independent, and memory-less fashion). We were able to reproduce the observed cluster distributions of five different types of channels in the membrane of excitable and tsA-201 cells in simulations using a computer model in which channels are {"}delivered{"} to the membrane at randomly assigned locations. The model's three parameters represent channel cluster nucleation, growth, and removal probabilities, the values of which were estimated based on our experimental measurements. We also determined the time course of cluster formation and membrane dwell time for CaV1.2 and TRPV4 channels expressed in tsA-201 cells to constrain our model. In addition, we elaborated a more complex version of our model that incorporated a self-regulating feedback mechanism to shape channel cluster formation. The strong inference we make from our results is that CaV1.2, CaV1.3, BK, and TRPV4 proteins are all randomly inserted into the plasma membranes of excitable cells and that they form homogeneous clusters that increase in size until they reach a steady state. Further, it appears likely that cluster size for a diverse set of membrane-bound proteins and a wide range of cell types is regulated by a common feedback mechanism.",
author = "Daisuke Sato and Gonzalo Hern{\'a}ndez-Hern{\'a}ndez and Collin Matsumoto and Sendoa Tajada and Moreno, {Claudia M.} and Dixon, {Rose E.} and Samantha O'Dwyer and Navedo, {Manuel F.} and Trimmer, {James S.} and Clancy, {Colleen E.} and Binder, {Marc D.} and Santana, {L. Fernando}",
year = "2019",
month = "9",
day = "2",
doi = "10.1085/jgp.201912327",
language = "English (US)",
volume = "151",
pages = "1116--1134",
journal = "Journal of General Physiology",
issn = "0022-1295",
publisher = "Rockefeller University Press",
number = "9",

}

TY - JOUR

T1 - A stochastic model of ion channel cluster formation in the plasma membrane

AU - Sato, Daisuke

AU - Hernández-Hernández, Gonzalo

AU - Matsumoto, Collin

AU - Tajada, Sendoa

AU - Moreno, Claudia M.

AU - Dixon, Rose E.

AU - O'Dwyer, Samantha

AU - Navedo, Manuel F.

AU - Trimmer, James S.

AU - Clancy, Colleen E.

AU - Binder, Marc D.

AU - Santana, L. Fernando

PY - 2019/9/2

Y1 - 2019/9/2

N2 - Ion channels are often found arranged into dense clusters in the plasma membranes of excitable cells, but the mechanisms underlying the formation and maintenance of these functional aggregates are unknown. Here, we tested the hypothesis that channel clustering is the consequence of a stochastic self-assembly process and propose a model by which channel clusters are formed and regulated in size. Our hypothesis is based on statistical analyses of the size distributions of the channel clusters we measured in neurons, ventricular myocytes, arterial smooth muscle, and heterologous cells, which in all cases were described by exponential functions, indicative of a Poisson process (i.e., clusters form in a continuous, independent, and memory-less fashion). We were able to reproduce the observed cluster distributions of five different types of channels in the membrane of excitable and tsA-201 cells in simulations using a computer model in which channels are "delivered" to the membrane at randomly assigned locations. The model's three parameters represent channel cluster nucleation, growth, and removal probabilities, the values of which were estimated based on our experimental measurements. We also determined the time course of cluster formation and membrane dwell time for CaV1.2 and TRPV4 channels expressed in tsA-201 cells to constrain our model. In addition, we elaborated a more complex version of our model that incorporated a self-regulating feedback mechanism to shape channel cluster formation. The strong inference we make from our results is that CaV1.2, CaV1.3, BK, and TRPV4 proteins are all randomly inserted into the plasma membranes of excitable cells and that they form homogeneous clusters that increase in size until they reach a steady state. Further, it appears likely that cluster size for a diverse set of membrane-bound proteins and a wide range of cell types is regulated by a common feedback mechanism.

AB - Ion channels are often found arranged into dense clusters in the plasma membranes of excitable cells, but the mechanisms underlying the formation and maintenance of these functional aggregates are unknown. Here, we tested the hypothesis that channel clustering is the consequence of a stochastic self-assembly process and propose a model by which channel clusters are formed and regulated in size. Our hypothesis is based on statistical analyses of the size distributions of the channel clusters we measured in neurons, ventricular myocytes, arterial smooth muscle, and heterologous cells, which in all cases were described by exponential functions, indicative of a Poisson process (i.e., clusters form in a continuous, independent, and memory-less fashion). We were able to reproduce the observed cluster distributions of five different types of channels in the membrane of excitable and tsA-201 cells in simulations using a computer model in which channels are "delivered" to the membrane at randomly assigned locations. The model's three parameters represent channel cluster nucleation, growth, and removal probabilities, the values of which were estimated based on our experimental measurements. We also determined the time course of cluster formation and membrane dwell time for CaV1.2 and TRPV4 channels expressed in tsA-201 cells to constrain our model. In addition, we elaborated a more complex version of our model that incorporated a self-regulating feedback mechanism to shape channel cluster formation. The strong inference we make from our results is that CaV1.2, CaV1.3, BK, and TRPV4 proteins are all randomly inserted into the plasma membranes of excitable cells and that they form homogeneous clusters that increase in size until they reach a steady state. Further, it appears likely that cluster size for a diverse set of membrane-bound proteins and a wide range of cell types is regulated by a common feedback mechanism.

UR - http://www.scopus.com/inward/record.url?scp=85071784597&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85071784597&partnerID=8YFLogxK

U2 - 10.1085/jgp.201912327

DO - 10.1085/jgp.201912327

M3 - Article

C2 - 31371391

AN - SCOPUS:85071784597

VL - 151

SP - 1116

EP - 1134

JO - Journal of General Physiology

JF - Journal of General Physiology

SN - 0022-1295

IS - 9

ER -