Voltage Gated K Channels in Lipid Rafts Possible Involvement in Local Regulatory Processes

Kv1.3 channels [104,105], the dominant voltage-gated potassium channels of T lymphocytes, play key roles in the control of membrane potential and calcium signaling, thereby affecting signal transduction pathways leading to the antigen-induced activation of these cells [106,107].

Activation of T cells through the TCR generates an oscillatory Ca2+ signal, which is created by a release from the Ca2+-storage compartments of the endoplasmic reticulum (ER) triggered by IP3 and consequential Ca2+ influx from the extracellular space [108]. The depolarizing Ca2+ influx must be counterbalanced by the activation of K+ channels, clamping the membrane potential at negative values and thereby providing a sufficient driving force for further Ca2+ entry. Voltage-gated K+ (Kv) channels form highly K+-selective pores that are conformationally switched open or closed by changes in membrane voltage [109]. In addition to the classical synapse-forming molecules, recently we described the recruitment of Kv1.3 to the immunological synapse [110], which may be mediated by its association with lipid rafts [111,112]. Elevation of the cholesterol content of the membrane modulated the gating properties of these channels [111]. By using confocal laser scanning microscopy (CLSM) and FRET, we have demonstrated clustering of Kv1.3 channels and their co-localization with the TCR/CD3 complex in Jurkat cells and human peripheral CTLs [110,113], indicating a possible crosstalk between the TCR signaling complex and Kv1.3. In nonengaged CTLs, small patches containing Kv1.3 and

TCR/CD3 complexes were evenly distributed on the cell surface, whereas they were both enriched at the IS formed at the CTL-target cell interface while maintaining their molecular proximity [110]. This is in accordance with biochemical studies suggesting the interaction of Kv1.3 channels with protein kinases, Lck and PKC, as well as various adaptor molecules, such as hDlg, PSD-95 (95 kDa postsynaptic density protein), KvP2, ZIP1 (PKC-Ç-interacting protein 1) and ZIP2, and the co-receptor CD4 (for reviews, see [107,114,115]). Physical association of Kv1.3 channels with the TCR might underline the importance of previous findings, in which regulation of Kv1.3 function by protein tyrosine kinase- and PKC-dependent phosphorylation was described. Besides the possibility of Kv1.3 channel regulation during formation of the IS, and the consequent modulation of Ca2+ signaling, localization of Kv1.3 in the IS raises the possibility of reciprocal regulation of IS function by nearby Kv1.3 [115]. For example, conformational changes in membrane proteins driven by the membrane potential might affect the antigen-recognition process [11,116], or local K+ efflux through Kv1.3 might activate the function of Printegrin, a possible determinant of the stability of the immunological synapse [117].

In addition to Kv1.3 channels, a whole class of voltage-gated Kv K+ channels are targeted to lipid rafts, a finding which bridges a gap between classical molecular immunology and electrophysiology (for a review, see [112]).

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