Open states of nuclear envelope ion channels in cardiac myocytes

Prevalent nucleocytoplasmic transport theory views flow of monoatomic ions as completely unrestricted, resulting from the presence of large diameter pore complexes (NPCs) that perforate, but hold together, the two separate membranes of the nuclear envelope (NE). However, three lines of investigations indicate that, at least in some cell types, monoatomic ion flow is restricted. (i) Patch clamp reveals quantized, ion channel-like activity in several NE preparations; activity thought to result from nuclear ion channels (NICs) connected to NPCs. (ii) Ratiometric fluorescence microscopy demonstrates that ions, as well as small molecules relevant to signal transduction, do distribute as if there is a NE barrier. (iii) Electron microscopy shows that NPCs contain material that behaves like a plug. NICs' large conductance (up to 1,000 pS) makes them a major determinant of nuclear ion concentrations which, in turn, influence nuclear processes. Therefore, NICs are an important modulating force of gene and transcriptional activities--two major determinants of gene expression. As nuclear processes may take from seconds (e.g., signaling) to minutes (e.g., transcription), the time the channels dwell in the ion-conducting open state is relevant to understanding NICs' role in nuclear function. Consequently, dwell-times and lifetimes of open NIC states were studied in 61 patch-clamped adult mouse cardiac myocyte nuclei. Upon voltage stimulation, NICs opened to main states of large conductance (281 +/- 198 pS, range = 120-490 pS, n = 55) and wide-range mean dwell-times (approximately 100 msec, 1-10 sec, and min). Closed states (0 pS) also had widely distributed mean dwell-times (approximately 100 msec, 1-10 sec, and min). Putative open substates (37 +/- 11 pS, range = 25-50, pS, n = 6) of high bursting frequency (< 1 msec) were observed without intervening main states (approximately 5% of patches). Fast (approximately 0.1 msec) and slow (approximately 10 msec) state-transitions were also detected. These observations suggest a role of NICs in mediating cytoplasmic signal control of cardiomyocyte gene expression.