Characterization of a Ca2+-activated Nonselective Cation Channel during Dedifferentiation of Cultured Rat Ventricular Cardiomyocytes

Abstract

Cardiac hypertrophy is associated with electrical activity modifications, including sustained depolarization, that lead to a propensity for arrhythmias. The ionic currents underlying the sustained depolarization are not well defined. Similar modifications were reported on adult rat cardiomyocytes in primary culture undergoing dedifferentiation. Using the single-channel measurements on these cells, we identified the appearance of a Ca2+-activated nonselective cation channel (NSCCa) during the dedifferentiation process. In excised inside-out patches the channel presented a linear I/V relationship with a conductance of 26.5 pS. It was equally selective for Na+ and K+ and impermeable to Cl- and Ca2+ ions. The open probability increased with depolarization and with rise in intracellular calcium concentration. The channel activity was reduced by intracellular ATP and suppressed by flufenamic acid. Channel detection increased after incubation with a purinergic receptor agonist (ATPgS) or a PKC activator (PMA). Furthermore, occurrence of the channel developed during the culture. Absent at one day in vitro (d.i.v.), channel activity was present in 5, 46, 27 and 19% of patches after 4, 7, 14 and 21 d.i.v., respectively. We suggest that the channel may be associated with pro-arrhythmic signaling, in particular during the release of transmitters from autonomic nerve endings in the hypertrophied hearts.

Regulation of the Ca2+ Sensitivity of the Nonselective Cation Channel TRPM4

“…activation of TRPV1 by capsaicin, heat, protons, or anandamide (19,20). A sensitizing effect of PKC stimulation on native TRPM4-like channels has been shown recently (21,22 cannot fully substitute for Ca 2ϩ in TRPM4 activation (3). A small activating effect of Sr 2ϩ has also been observed in the related TRPM5 channel, which has been interpreted as a possible direct effect on channel opening, rather than a CaM-dependent action, because CaM modulators did not affect TRPM5 activation (11).…”

Activation of a Calcium-Activated Cation Current During Epileptiform Discharges and Its Possible Role in Sustaining Seizure-Like Events in Neocortical Slices

“…I can can potentially serve as such a mechanism. The CAN channels have a low affinity for [Ca 2ϩ ] i , and their activation probably requires [Ca 2ϩ ] i to reach micromolar concentrations (Cho et al 2003;Guinamard et al 2002;Miyashita et al 2001). Inter-ictal-like discharges and seizure-like events evoke very large dendritic [Ca 2ϩ ] i transients, which reach values of 13.3-71.0 M in different dendritic regions (Schiller 2002) and far exceed the [Ca 2ϩ ] i values reached under physiological activation (compare with Schiller et al 1995 andSchiller 2002).…”

Somato-dendritic mechanisms underlying the electrophysiological properties of hypothalamic magnocellular neuroendocrine cells: A multicompartmental model study

“…I CAN appears to have higher calcium sensitivity than other Ca 2+ -activated currents, such as I BK and I SK (Zhu et al 2004). The voltage-dependence of opening of CAN channels recently was reported in several excitable cells, including in rat and human cardiomyocytes (Guinamard et al 2002(Guinamard et al , 2004 and in hamster vomeronasal sensory neurons (Liman 2003). We included these voltage-dependent properties in our mathematical description of I CAN (see Appendix).…”