Nanojunctions: Specificity of Ca2+ signalling requires nano-scale architecture of intracellular membrane contact sites

Abstract

Specificity of control over virtually all essential cellular functions by Ca2+ is based on the existence of separated, autonomic signaling modules. Spatiotemporal definition of Ca2+ signals involves the assembly of signaling complexes within the nano-architecture of contact sites between the sarco/endoplasmic (SR/ER) reticulum and the plasma membrane (PM). While the requirement of precise spatial assembly and positioning of the junctional signaling elements is well documented, the role of the nano-scale membrane architecture itself, as an ion reflecting confinement of the signaling unit, remains as yet elusive. Utilizing the NCX1/SERCA2-mediated ER Ca2+ refilling process as a junctional signalling paradigm, we provide here the first evidence for an indispensable cellular function of the junctional membrane architecture. Our stochastic modeling approach demonstrates that junctional ER Ca2+refilling operates exclusively at nano-scale membrane spacing, with a strong inverse relationship between junctional width and signaling efficiency. Our model predicts a breakdown of junctional Ca2+ signaling with loss of reflecting membrane confinement, irrespective of the spatial positioning of the molecular signaling elements. Alterations in the molecular and nano-scale membrane organization at organelle-PM contacts are suggested as new concept in pathophysiology.