Abstract
One of the fastest cellular responses following activation of epidermal growth factor receptor is an increase in intracellular Ca2+ concentration. This event is attributed to a transient Ca2+ release from internal stores and Ca2+ entry from extracellular compartment. Store-operated Ca2+ channels are defined the channels activated in response to store depletion. In the present study, we determined whether epidermal growth factor activated store-operated Ca2+ channels and further, whether depletion of internal Ca2+ stores was required for the epidermal growth factor-induced Ca2+ entry in human glomerular mesangial cells. We found that 100 nm epidermal growth factor activated a Ca2+-permeable channel that had identical biophysical and pharmacological properties to channels activated by 1 microm thapsigargin in human glomerular mesangial cells or A431 cells. The epidermal growth factor-induced Ca2+ currents were completely abolished by a selective phospho-lipase C inhibitor, U73122. However, xestospongin C, a specific inositol 1,4,5-trisphosphate receptor inhibitor, did not affect the membrane currents elicited by epidermal growth factor despite a slight reduction in background currents. Following emptying of internal Ca2+ stores by thapsigargin, epidermal growth factor still potentiated the Ca2+ currents as determined by the whole-cell patch configuration. Furthermore, epidermal growth factor failed to trigger measurable Ca2+ release from endoplasmic reticulum. However, another physiological agent linked to phospholipase C and inositol 1,4,5-trisphosphate cascade, angiotensin II, produced a striking Ca2+ transient. These results indicate that epidermal growth factor activates store-operated Ca2+ channels through an inositol 1,4,5-trisphosphate-independent, but phospholipase C-dependent, pathway in human glomerular mesangial cells.
Highlights
One of the fastest cellular responses following activation of epidermal growth factor receptor is an increase in intracellular Ca2؉ concentration
We found that 100 nM epidermal growth factor activated a Ca2؉-permeable channel that had identical biophysical and pharmacological properties to channels activated by 1 M thapsigargin in human glomerular mesangial cells or A431 cells
We previously found that Epidermal growth factor (EGF) activated Ca2ϩ-permeable channels that possessed similar biophysical and pharmacological properties to those of store-operated Ca2ϩ channel (SOC) at single channel level in human glomerular mesangial cells (HMC) [9, 10]
Summary
One of the fastest cellular responses following activation of epidermal growth factor receptor is an increase in intracellular Ca2؉ concentration This event is attributed to a transient Ca2؉ release from internal stores and Ca2؉ entry from extracellular compartment. Another physiological agent linked to phospholipase C and inositol 1,4,5-trisphosphate cascade, angiotensin II, produced a striking Ca2؉ transient These results indicate that epidermal growth factor activates store-operated Ca2؉ channels through an inositol 1,4,5-trisphosphate-independent, but phospholipase C-dependent, pathway in human glomerular mesangial cells. We previously found that EGF activated Ca2ϩ-permeable channels that possessed similar biophysical and pharmacological properties to those of SOC at single channel level in human glomerular mesangial cells (HMC) [9, 10] It remains uncertain whether the EGF-evoked Ca2ϩ influx is dependent on store depletion or other second messengers activated in response to EGF. We provide electrophysiological and pharmacological evidence that EGF activates SOC by a PLC-dependent but IP3 receptor (IP3R) independent pathway in HMC
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