Homeostatic Regulation of Kv1.2 Potassium Channel Trafficking by Cyclic AMP

Abstract

The Shaker family potassium channel, Kv1.2, is a key determinant of membrane excitability in neurons and cardiovascular tissue. Kv1.2 is subject to multiple forms of regulation and therefore integrates cellular signals involved in the homeostasis of excitability. The cyclic AMP/protein kinase A (PKA) pathway enhances Kv1.2 ionic current; however, the mechanisms for this are not fully known. Here we show that cAMP maintains Kv1.2 homeostasis through opposing effects on channel trafficking. We found that Kv1.2 is regulated by two distinct cAMP pathways, one PKA-dependent and the other PKA-independent. PKA inhibitors elevate Kv1.2 surface levels, suggesting that basal levels of cAMP control steady-state turnover of the channel. Elevation of cAMP above basal levels also increases the amount of Kv1.2 at the cell surface. This effect is not blocked by PKA inhibitors, but is blocked by inhibition of Kv1.2 endocytosis. We conclude that Kv1.2 levels at the cell surface are kept in dynamic balance by opposing effects of cAMP.The voltage-gated potassium channel, Kv1.2, plays an important role in modulating membrane potential, and its effects are associated with a wide range of human pathologies. In the brain, Kv1.2 is associated with seizure activity (1, 2). In dorsal root ganglion neurons, Kv1.2 plays a central role in nociception and is involved in the generation of neuropathic pain (3-5). In cardiac and vascular smooth muscle, Kv1.2 activity is associated with increased vascular tone and hypertension (6 -8). Kv1.2 activity within the cell is not static, but is instead subject to both positive and negative regulation (9, 10). Disruption of that regulation may underlie some of the pathologies associated with Kv1.2 function. Therefore, elucidating the mechanisms of Kv1.2 regulation is essential for understanding a broad range of pathological conditions.

Axonal targeting of Caspr2 in hippocampal neurons via selective somatodendritic endocytosis

“…Caspr2 is implicated in the clustering of Kv1 channels at juxtaparanodes (Traka et al, 2003;Poliak et al, 2003). Protein kinases have direct and indirect effects on the membrane translocation and activity of the voltagegated potassium channels (Yang et al, 2007;Connors et al, 2008). Our data indicate that PKC phosphorylation influences Caspr2 trafficking.…”

Rapid Homeostatic Plasticity of Intrinsic Excitability in a Central Pattern Generator Network Stabilizes Functional Neural Network Output

“…Given the potential nonspecific effects of pharmacological treatment, we cannot rule out at least some role for a kinase in this pathway. For example, Kv1.2 potassium channels are known to be affected by cAMP/protein kinase A pathways which enhance their conductance, in part by altering trafficking of these channels (Connors et al, 2008). Our staurosporine treatment may result in only partial inhibition of PKA (Rüegg and Burgess, 1989), which could explain the intermediate effects seen on the A-type current compensation.…”

“…The corresponding mechanism responsible for compensatory increases in I A (Fig. 6) is presently unknown, but is likely to involve distinct mechanisms for monitoring excitability (Dirnagl et al, 2003), as well as other candidate mechanisms that alter A-type conductances (Connors et al, 2008). Finally, we hypothesize that positive coregulation of mRNA numbers for channel genes may ultimately provide a reservoir of channel protein (Fig.…”

Endocytic Regulation of Voltage-Dependent Potassium Channels in the Heart

“…The lysophosphatidic acid receptor (LPAR) has been shown to elicit Kv1.2 endocytosis through the RhoA/ROCK signaling pathway (10). In addition to the tyrosine kinase-dependent endocytosis, trafficking of Kv1.2 has been reported to be regulated by cAMP (11). Further, in contrast to stimulus-induced endocytosis, steady-state endocytosis of Kv1.2 has been suggested to be caveolin-dependent (10).…”