Kv Channel Activity and Ca2 Homeostasis in Intestinal Epithelial Cells

Increasing evidence shows that activity of Kv channels controls E that regulates [Ca2+]cyt concentration by governing the driving force for Ca2+ influx (5,9). At the cellular level, [Ca2+]cyt is derived from two sources—external and internal stores (12-14). Ca2+ can enter from outside the cell by passing through channels that span the external barrier, plasma membrane, and also be released from internal Ca2+ stores (endoplasmic or sarcoplasmic reticuli). Ca2+ influx depends on the Ca2+ driving force, or the electrochemical gradient across the plasma membrane. Although the chemical gradient, the ratio of extracellular [Ca2+] ([Ca2+]o) to [Ca2+]c t, and the Ca2+ equilibrium potential, ECa {ECa = 12.5 ln ([Ca2+]o/ [Ca2^) = 117-131 mV at 25°C} are constant, the Ca2+ driving force is mainly determined by the electrical gradient, the difference between E and Er (E - Er ). In other words, E is a major determinant m Ca v m Ca ' m -J

of the driving force for Ca2+ influx.

By controlling the Ca2+ driving force, Em is an important regulator of [Ca2+]c t in nonexcitable cells including epithelial cells and lymphocytes. Membrane depolarization, such as after polyamine depletion, decreases the Ca2+ driving force and inhibits Ca2+ influx. In contrast, membrane hyperpolarization after increased polyamines increases the Ca2+ driving force and enhances Ca2+ influx. Therefore, in the cells that do not express L-type voltage-dependent Ca2+ channels (VDCC), Ca2+ influx is decreased by membrane depolarization but increased by membrane hyperpolarization.

Fig. 1. Effect of depletion of cellular polyamines by a-difluoromethylornithine (DFMO) on mRNA expression of voltage-gated K+ (Kv)1.1 channel (A), whole cell Kv currents (B), and resting membrane potential (C) in intestinal epithelial cells (IEC-6 line). Cells were grown in the Dulbecco's modified Eagle's medium containing 5% dialyzed fetal bovine serum and 5 mM DFMO with or without 5 ^Mspermidine (SPD) for 4 d. *, + p < 0.05 compared with control and DFMO alone, respectively.

Fig. 1. Effect of depletion of cellular polyamines by a-difluoromethylornithine (DFMO) on mRNA expression of voltage-gated K+ (Kv)1.1 channel (A), whole cell Kv currents (B), and resting membrane potential (C) in intestinal epithelial cells (IEC-6 line). Cells were grown in the Dulbecco's modified Eagle's medium containing 5% dialyzed fetal bovine serum and 5 mM DFMO with or without 5 ^Mspermidine (SPD) for 4 d. *, + p < 0.05 compared with control and DFMO alone, respectively.

Nonetheless, in excitable cells such as neurons, cardiomyocytes, and muscle cells, VDCC that are opened by membrane depolarization are the major pathway for Ca2+ influx (7). In contrast to the voltage-independent pathway for Ca2+ influx in non-excitable cells, membrane depolarization opens VDCC and thus increases [Ca2+]cyt in excitable cells.

Em is primarily determined by the K+ permeability and K+ gradient across the plasma membrane (7). Because the K+ gradient is maintained by Na+-K+ adenosine triphosphatase, the K+ permeability is directly related to the activity and number of membrane K+ channels. Kv channels are a major determinant of resting Em in many types of cells. When K+ channels close or the total numbers of total K+ channels decrease, Em becomes less negative (i.e., depolarization). When K+ channels open or the numbers of total K+ channels rise, Em becomes more negative (i.e., hyperpolarization) (7,9). Therefore, inhibition of K+ channel gene expression in polyamine-deficient cells would decrease the number of K+ channels and attenuate K+ channel activity. The subsequent membrane depolarization decreases the Ca2+ driving force, and thus inhibits Ca2+ influx. Because Ca2+ entry is a major source for [Ca2+]cyt, inhibition of Ca2+ influx would reduce [Ca2+]cyt in cells lacking VDCC (7).

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