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

Spatio-temporal definition of Ca²⁺ signals involves the assembly of signaling complexes within the nano-architecture of contact sites between the sarco/endoplasmic reticulum (SR/ER) 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 signalling unit, remains as yet elusive. Utilizing the Na⁺/Ca²⁺ Exchanger-1 / SR/ER Ca²⁺ ATPase-2-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. In addition we consider interactions between Ca²⁺ and the phospholipid membrane surface, which may support interfacial Ca²⁺ transport and promote receptor targeting. Alterations in the molecular and nano-scale membrane organization at organelle-PM contacts are suggested as a new concept in pathophysiology.