Computational investigation of IP diffusion.

Inositol 1,4,5-trisphosphate (IP) plays a key role in calcium signaling. After stimulation, it diffuses from the plasma membrane where it is produced to the endoplasmic reticulum where its receptors are localized. Based on in vitro measurements, IP was long thought to be a global messenger characterized by a diffusion coefficient of ~ 280 μms. However, in vivo observations revealed that this value does not match with the timing of localized Ca increases induced by the confined release of a non-metabolizable IP analog. A theoretical analysis of these data concluded that in intact cells diffusion of IP is strongly hindered, leading to a 30-fold reduction of the diffusion coefficient. Here, we performed a new computational analysis of the same observations using a stochastic model of Ca puffs. Our simulations concluded that the value of the effective IP diffusion coefficient is close to 100 μms. Such moderate reduction with respect to in vitro estimations quantitatively agrees with a buffering effect by non-fully bound inactive IP receptors. The model also reveals that IP spreading is not much affected by the endoplasmic reticulum, which represents an obstacle to the free displacement of molecules, but can be significantly increased in cells displaying elongated, 1-dimensional like geometries.