Abstract
Calcium (
) 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 (
), diffusible 
, 
receptors (
s), endoplasmic reticulum (ER) 
leak, and ER pump (SERCA) on ER. 
is released from ER stores via 
s upon binding of 
and 
. This results in 
-induced-
-release (CICR) and increases 
spread. At least two modes of 
wave spread have been suggested: a continuous mode based on presumed relative homogeneity of ER within the cell and a pseudo-saltatory model where 
regeneration occurs at discrete points with diffusion between them. We compared the effects of three patterns of hypothesized 
distribution: (1) continuous homogeneous ER, (2) hotspots with increased 
density (
hotspots), and (3) areas of increased ER density (ER stacks). All three modes produced 
waves with velocities similar to those measured in vitro (approximately 50–90 
m /sec). Continuous ER showed high sensitivity to 
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 
hotspots and stacks. Increasing the apparent diffusion coefficient of 
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 
wave amplitude and duration. Our modeling suggests that pharmacological targeting of 
s and SERCA could allow modulation of 
wave propagation in diseases where 
dysregulation has been implicated.