Chapter 8
Computer Simulations of
Hippocampal Mossy Fiber Cleft
Zinc Movements
Johnattan C.S. Freitas, João N. Miraldo,
Carlos Manuel M. Matias, Fernando D.S. Sampaio dos Aidos,
Paulo J. Mendes, José C. Dionísio, Rosa M. Santos,
Luís M. Rosário, Rosa M. Quinta-Ferreira
and Emília Quinta-Ferreira
Abstract
Zinc ions have key regulatory, structural, and catalytic functions and mediate a
variety of intra- and intercellular processes. The hippocampal mossy fiber boutons
contain large amounts of free or loosely bound vesicular zinc, which can be coreleased with glutamate. Zinc can interact with a variety of ionic channels (NVDCCs, L-VDCCs, K ATP ), glutamate receptors (AMPA, KA, NMDA 2A, 2B), glutamate transporters (GLAST, EAAT4), and molecules (ATP). The dynamic properties
of cleft free, complexed, and total zinc were addressed, considering the known
concentration and affinity of various cleft zinc sensitive sites, mainly in the postsynaptic area and in glial cells. The computer model included three different zinc
release processes, with short, medium, and long duration, described, like the uptake
ones, by alpha functions. The results suggest that, depending on the amount of
release, zinc clearance is largely due, either, to zinc binding to NMDA 2A receptor
sites or to glial GLAST transporters.
Keywords: synaptic modeling, zinc-binding sites and complexes, glutamate
receptors and transporters, zinc clearance and uptake, CA3 area
1. Introduction
Zinc is one of the most concentrated trace elements in the brain, being essential for
normal cellular function and signaling processes in the central nervous system (CNS)
[1–3]. This system contains very large amounts of chelatable or free zinc [4], mainly
in the synaptic vesicles of excitatory nerve terminals [5], essentially in the hippocampal mossy fibers from CA3 area [1, 2]. After release, zinc affects the behavior of
several voltage-gated and receptor-operated ionic channels [6–12]. The action of zinc
in different types of receptors and channels depends essentially on two factors: their
concentration in the synapses and their affinity for zinc. A clear understanding of the
action of zinc in individual binding sites is restricted by the complexity of the synaptic
transmission process. To further investigate this zinc role, a computational model was
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Computer Simulations of
Hippocampal Mossy Fiber Cleft
Zinc Movements
Johnattan C.S. Freitas, João N. Miraldo,
Carlos Manuel M. Matias, Fernando D.S. Sampaio dos Aidos,
Paulo J. Mendes, José C. Dionísio, Rosa M. Santos,
Luís M. Rosário, Rosa M. Quinta-Ferreira
and Emília Quinta-Ferreira
Abstract
Zinc ions have key regulatory, structural, and catalytic functions and mediate a
variety of intra- and intercellular processes. The hippocampal mossy fiber boutons
contain large amounts of free or loosely bound vesicular zinc, which can be coreleased with glutamate. Zinc can interact with a variety of ionic channels (NVDCCs, L-VDCCs, K ATP ), glutamate receptors (AMPA, KA, NMDA 2A, 2B), glutamate transporters (GLAST, EAAT4), and molecules (ATP). The dynamic properties
of cleft free, complexed, and total zinc were addressed, considering the known
concentration and affinity of various cleft zinc sensitive sites, mainly in the postsynaptic area and in glial cells. The computer model included three different zinc
release processes, with short, medium, and long duration, described, like the uptake
ones, by alpha functions. The results suggest that, depending on the amount of
release, zinc clearance is largely due, either, to zinc binding to NMDA 2A receptor
sites or to glial GLAST transporters.
Keywords: synaptic modeling, zinc-binding sites and complexes, glutamate
receptors and transporters, zinc clearance and uptake, CA3 area
1. Introduction
Zinc is one of the most concentrated trace elements in the brain, being essential for
normal cellular function and signaling processes in the central nervous system (CNS)
[1–3]. This system contains very large amounts of chelatable or free zinc [4], mainly
in the synaptic vesicles of excitatory nerve terminals [5], essentially in the hippocampal mossy fibers from CA3 area [1, 2]. After release, zinc affects the behavior of
several voltage-gated and receptor-operated ionic channels [6–12]. The action of zinc
in different types of receptors and channels depends essentially on two factors: their
concentration in the synapses and their affinity for zinc. A clear understanding of the
action of zinc in individual binding sites is restricted by the complexity of the synaptic
transmission process. To further investigate this zinc role, a computational model was
111