Neuronal calcium wave propagation varies with changes in endoplasmic reticulum parameters: a computer model.
Calcium (Ca²⁺) waves provide a complement to neuronal electrical signaling, forming a key part of a neuron's second messenger system. We developed a reaction-diffusion model of an apical dendrite with diffusible inositol triphosphate (IP₃), diffusible Ca²⁺, IP₃ receptors (IP₃Rs), endoplasmic reticulum (ER) Ca²⁺ leak, and ER pump (SERCA) on ER. Ca²⁺ is released from ER stores via IP₃Rs upon binding of IP₃ and Ca²⁺. This results in Ca²⁺-induced-Ca²⁺-release (CICR) and increases Ca²⁺ spread. At least two modes of Ca²⁺ wave spread have been suggested: a continuous mode based on presumed relative homogeneity of ER within the cell and a pseudo-saltatory model where Ca²⁺ regeneration occurs at discrete points with diffusion between them. We compared the effects of three patterns of hypothesized IP₃R distribution: (1) continuous homogeneous ER, (2) hotspots with increased IP₃R density (IP₃R hotspots), and (3) areas of increased ER density (ER stacks). All three modes produced Ca²⁺ waves with velocities similar to those measured in vitro (approximately 50-90 μm /sec). Continuous ER showed high sensitivity to IP₃R density increases, with time to onset reduced and speed increased. Increases in SERCA density resulted in opposite effects. The measures were sensitive to changes in density and spacing of IP₃R hotspots and stacks. Increasing the apparent diffusion coefficient of Ca²⁺ substantially increased wave speed. An extended electrochemical model, including voltage-gated calcium channels and AMPA synapses, demonstrated that membrane priming via AMPA stimulation enhances subsequent Ca²⁺ wave amplitude and duration. Our modeling suggests that pharmacological targeting of IP₃Rs and SERCA could allow modulation of Ca²⁺ wave propagation in diseases where Ca²⁺ dysregulation has been implicated.
Department of Physiology and Pharmacology, SUNY Downstate, Brooklyn, NY, 11203, and Department of Neurobiology, Yale University School of Medicine, New Haven, CT 06510, U.S.A. samn@neurosim.downstate.edu.
Samuel A
SA
Neymotin
Robert A
RA
McDougal
Mohamed A
MA
Sherif
Christopher P
CP
Fall
Michael L
ML
Hines
William W
WW
Lytton
D000818:Animals; D020864:Calcium Channels, N-Type / Q000502:physiology; D020013:Calcium Signaling / Q000502:physiology*; D003198:Computer Simulation; D004721:Endoplasmic Reticulum / Q000502:physiology*; D008959:Models, Neurological; D009474:Neurons / Q000648:ultrastructure*; D015221:Potassium Channels; D018091:Receptors, AMPA / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism
D020864:Calcium Channels, N-Type; D015221:Potassium Channels; D018091:Receptors, AMPA; D015222:Sodium Channels