Heterogeneous functional expression of the sustained inward Na+ current in guinea pig sinoatrial node cells
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The sustained inward Na+ current (I st) identified in the sinoatrial node (SAN) cell has been suggested to play a pivotal role in cardiac pacemaking. However, the composition of cells in the SAN is heterogeneous and cell-to-cell variability in the magnitude of I st remains to be fully characterized. The present study investigated the current density of I st in morphologically different types of pacemaker cells dissociated from guinea pig SAN. I st was preferentially detected in spontaneously active spindle or spider-shaped cells, but was less well expressed in larger-sized elongated spindle-type cells and practically absent in clearly striated atrial-like cells, despite clear expression of the funny current (I f). The current density of I st in spindle and spider cells varied from 0.7 to 1.6 pA pF−1 and was significantly reduced in non-beating cells with similar morphologies. By linear regression analysis, we identified a positive correlation between the current densities of I st and the L-type Ca2+ current (I Ca,L), which was specifically observed in spindle and spider cells. These cells exhibited a more negative voltage for half maximal I Ca,L activation than atrial-like cells, suggesting a variable ratio between CaV1.2- and CaV1.3-mediated I Ca,L in SAN cells. Consistent single-cell transcript measurements confirmed a higher relative expression of CaV1.3, which activates at more negative potentials, in spindle cells than in atrial-like cells. Taken together, these results can be interpreted as indicating that I st plays a specific role in primary pacemaker cells and that its presence is closely correlated with functional levels of CaV1.3-mediated I Ca,L.
KeywordsSinoatrial node cells Sustained inward current L-type Ca2+ current CaV1.3 Cellular heterogeneity
L-type Ca2+ current
Hyperpolarization-activated cation current
Sustained inward current
The authors are grateful to Dr. Matteo E. Mangoni and Dr. Jeorg Striessnig for fruitful discussions and encouragement.
F.T., D. W-G., and H.M. designed the study. F.T. performed all experiments and analyzed the data. F.T. drafted the manuscript and all authors critically revised it for technical and important contents.
The project was supported by the Grant-in-Aid for Scientific Research (C) 23590258, 26460295 and 17K08537 from the Japan Society for the Promotion of Science (to F.T.).
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