Reconstruction of Cell Surface Densities of Ion Pumps, Exchangers, and Channels from mRNA Expression, Conductance Kinetics, Whole-Cell Calcium, and Current-Clamp Voltage Recordings, with an Application to Human Uterine Smooth Muscle Cells

摘要

Author Summary A well-known problem in electrophysiologal modeling is that the parameters of the gating kinetics of the ion channels cannot be uniquely determined from observed behavior at the cellular level. One solution is to employ simplified 'macroscopic' currents that mimic the behavior of aggregates of distinct entities at the protein level. The gating parameters of each channel or pump can be determined by studying it in isolation, leaving the general problem of finding the densities at which the channels occur in the plasma membrane. We propose an approach, which we apply to uterine smooth muscle cells, whereby we constrain the list of possible entities by means of transcriptomics and chart the indeterminacy of the problem in terms of the kernel of the corresponding linear transformation. A graphical representation of this kernel visualises the functional redundancy of the system. We show that the role of certain conductances can be fulfilled, or compensated for, by suitable combinations of other conductances; this is not always the case, and such 'non-substitutable' conductances can be regarded as functionally non-redundant. Electrogenic entities belonging to the latter category are suitable putative clinical targets.