Caffeine-induced Ca
2C
oscillations
in type I horizontal cell of carp retina:
A mathematical model
Ting Lv, Pu-Ming Zhang, Hai-Qing Gong, and Pei-Ji Liang
School of Biomedical Engineering; Shanghai Jiao Tong University; Shanghai, China
Keywords: Ca
2C
oscillations, caffeine, computational model, retinal horizontal cell, ryanodine receptor, store-operated channel
Abbreviations: 2-APB, 2-Aminoethoxydiphenyl borate; [Ca
2C
]
ER
, Free Ca
2C
concentration inside the lumen of the ER; [Ca
2C
]
i
,
Intracellular free Ca
2C
concentration; ANOVA, Analysis of variance; CICR, Ca
2C
-induced Ca
2C
release; ER, Endoplasmic reticulum;
H1 HC, Type I horizontal cell; HC, Horizontal cell; L-VGCC, Ca
2C
channel; NCX, Na
C
/Ca
2C
exchanger; PM, Plasma membrane;
PMCA, Plasma membrane Ca
2C
-ATPase; RyR, Ryanodine receptor; SERCA, Sarco/endoplasmic reticulum Ca
2C
-ATPase; SNK,
Student-Newman-Keuls; SOC, Store-operated channel; SOCE, Store-operated Ca
2C
entry; STIM, Stromal interaction molecule;
TRP, Transient receptor potential.
Oscillations in intracellular free Ca
2C
concentration ([Ca
2C
]
i
) have been observed in a variety of cell types. In the
present study, we constructed a mathematical model to simulate the caffeine-induced [Ca
2C
]
i
oscillations based on
experimental data obtained from isolated type I horizontal cell of carp retina. The results of model analysis confirm the
notion that the caffeine-induced [Ca
2C
]
i
oscillations involve a number of cytoplasmic and endoplasmic Ca
2C
processes
that interact with each other. Using this model, we evaluated the importance of store-operated channel (SOC) in
caffeine-induced [Ca
2C
]
i
oscillations. The model suggests that store-operated Ca
2C
entry (SOCE) is elicited upon
depletion of the endoplasmic reticulum (ER). When the SOC conductance is set to 0, caffeine-induced [Ca
2C
]
i
oscillations are abolished, which agrees with the experimental observation that [Ca
2C
]
i
oscillations were abolished
when SOC was blocked pharmacologically, verifying that SOC is necessary for sustained [Ca
2C
]
i
oscillations.
Introduction
[Ca
2C
]
i
oscillations have been observed in a variety of cell
types.
1
The present study is focused on caffeine-induced [Ca
2C
]
i
oscillations in type I horizontal cell (H1 HC) of carp reti na. Hor-
izontal cells are interneurons in vertebrate retinas, which receive
glutamate input from photoreceptors. In carp H1 HC, [Ca
2C
]
i
increase is caused primarily by Ca
2C
release from intracellular
Ca
2C
store (basically the endoplasmic reticulum, ER) via ryano-
dine receptor (RyR) activation
2,3
and Ca
2C
influx from the extra-
cellular environment, while Ca
2C
removal depends on the
activities of the sarco/endoplasmic reticulum Ca
2C
-ATPase
(SERCA),
2-4
Na
C
/Ca
2C
exchanger (NCX)
5
and plasma mem-
brane Ca
2C
-ATPase (PMCA).
5
Ca
2C
imaging study with carp H1 HC revealed that [Ca
2C
]
i
oscillations could be induced when caffeine was applied at vari-
ous concentrations.
6
The application of caffeine activates RyR,
leading to ER Ca
2C
release and ER depletion. Subsequent ER
refilling, which should be required for the maintenance of
[Ca
2C
]
i
oscillations, is dependent on Ca
2C
entry via store-
operated channel (SOC). Hence RyR and SOC, together with
the Ca
2C
removal processes are the major components for caf-
feine-induced [Ca
2C
]
i
oscillations. However, how these compo-
nents interact with each other to give rise to [Ca
2C
]
i
oscillations
observed in H1 HC is unclear.
In the present study, a computational model based on biophysi-
cal properties of H1 HC was constructed to explore the underlying
mechanism(s) of caffeine-induced [Ca
2C
]
i
oscillations observed in
H1 HC of carp retina. Using this model, caffeine-induced [Ca
2C
]
i
oscillations were simulated. The concentration-dependent caffeine
effect on the pattern of [Ca
2C
]
i
oscillations was explored, relevant
contributions of RyR, SOC, L-type voltage-gated Ca
2C
channel
(L-VGCC), NCX, PMCA and SERCA for caffeine-induced
[Ca
2C
]
i
oscillations were suggested, and the importance of SOC in
caffeine-induced [Ca
2C
]
i
oscillations was evaluated.
Results
Simulating caffeine-induced [Ca
2C
]
i
oscillations in isolated
H1 HC
Figure 1A–C shows the experimental observations of caffeine-
induced [Ca
2C
]
i
oscillations of 3 representative H1 HCs in
© Ting Lv, Pu-Ming Zhang, Hai-Qing Gong, and Pei-Ji Liang
Correspondence to: Pei-Ji Liang; Email: pjliang@sjtu.edu.cn
Submitted: 07/26/2014; Revised: 09/05/2014; Accepted: 09/10/2014
http://dx.doi.org/10.4161/19336950.2014.965113
www.landesbioscience.com 509Channels
Channels 8:6, 509--518; November/December 2014; Published with license by Taylor & Francis Group, LLC
RESEARCH PAPER