SMIC can destabilize the diastolic membrane potential and trigger arrhythmias. Here, we show which ion channels SMIC is based on and which is the adequate mechanical stimulus. - Murine ventricular myocytes were attached to glass coverslips and deformed with a cell-attached glass stylus. Local axial stretch or compression destabilized the diastolic potential and induced extra systoles due to both activation of Gns (non-selective cation conductance) and deactivation of GK1 (inward rectifier). Activation of Gns was prevented by dialysis of TRPC5 antibodies. Immunolabeling indicated localization of TRPC6 and Kir2.3 exclusively in T-tubules. SMIC depended on misalignment of T-tubules but not on sarcomere lengthening, a result compatible with presence of SIAs during non-homogeneous activation (Ca2+ -waves, local ischemia) and their absence during physiological preload. Extent of SMIC increased with the amplitude of axial shear and reversed upon mechanical relaxation. SMIC was abolished by blocking integrins with RGD-I-peptides. Axial shear increased [Na+ ]c (sodium green fluorescence )and Gns both inside and outside the deformed parts of the myocyte. - In reference to our morphological data we attribute SMIC to misalignment of T-tubules; proteins in the T-tubular basal lamina may pull on integrins and thereby trigger the generation of a diffusible second messenger that modulates TRPC6 and Kir2.3 in the T-tubules of the whole cell.