Regulation of Kir2.1 channels by the Rho‐GTPase, Rac1

Abstract

Mutations in Kir2

p75 Regulates Purkinje Cell Firing by Modulating SK Channel Activity through Rac1

“…Rac1 has been shown to regulate K ϩ channel activities, such as the ethera-go-go-related potassium channel in a rat pituitary cell line (57), the inwardly rectifying K ϩ channel, Kir2.1 (12), and the ATP-sensitive K ϩ channels (58), but the underlying mechanisms can be quite different. Current literature suggests that Rac1 affects K ϩ channel function indirectly by regulating either channel trafficking to the plasma membrane through association with the actin cytoskeleton (59 -62) or channel internalization (12). Also, the p75-evoked activation of Rac1 could promote phosphatidylinositol 5-kinase activity for enhanced phosphatidylinositol 4,5-bisphosphate synthesis and, in turn, activation of GIRK channels (63).…”

“…Interestingly, the effect of RacGTP on synaptic function is not merely a consequence of spine morphology regulation. Rac1 signaling has been shown to affect ion channels, such as Kir2.1 (12), GABA A receptors (13), voltagegated Ca 2ϩ channels (VGCCs) (14), and GIRK channels (15) in the nervous system. These were thought to occur either through the effect of Rac1 on actin cytoskeleton (13) or its action on promoting the synthesis of phosphatidylinositol 4,5-bisphosphate (15).…”

Small G Proteins in the Cardiovascular System: Physiological and Pathological Aspects

“…Dominant negative Rac1 has been shown to strongly increase Kir2.1 current, while the constitutively active Rac1 had no significant effect (54). This effect resulted from Rac1-mediated reduction of basal internalization of the channels, leading to an increase in the number of Kir2.1 channels at the plasma membrane, without change of its global expression level (54). These data thus suggest that Rac1-mediated regulation of ERG or Kir2.1 channels can participate in the arrhythmogenic effect of Rac1 activation.…”

“…For example, active Rac1 mutant stimulates ERG channel activity, via a stimulatory action on the serine-threonine phosphatase PP5 (134,467). Dominant negative Rac1 has been shown to strongly increase Kir2.1 current, while the constitutively active Rac1 had no significant effect (54). This effect resulted from Rac1-mediated reduction of basal internalization of the channels, leading to an increase in the number of Kir2.1 channels at the plasma membrane, without change of its global expression level (54).…”

Biological Pacemaker – Main Ideas and Optimization

“…Defective membrane trafficking due to mutated Kir2.1/HCN channels has been linked to cardiac arrhythmias (Dhamoon & Jalife, 2005;Herrmann et al, 2007;Baruscotti et al, 2010). Furthermore, endogenous proteins, such as small GTPase Rho1/Rac1, have been found to modulate Kir2.1 surface expression (Boyer et al, 2009). We have recently discovered that tyrosine phosphorylation of HCN channels mediated by Src kinases and receptor protein tyrosine phosphatase alpha can significantly alter the surface expression of HCN2/HCN4 channels (Huang et al, 2008;Lin et al, 2009).…”