PT  - JOURNAL ARTICLE
AU  - Michael N. Nitabach
AU  - D. Alberto Llamas
AU  - Ian J. Thompson
AU  - Kerry A. Collins
AU  - Todd C. Holmes
TI  - Phosphorylation-Dependent and Phosphorylation-Independent Modes of Modulation of &lt;em&gt;Shaker&lt;/em&gt; Family Voltage-Gated Potassium Channels by Src Family Protein Tyrosine Kinases
AID  - 10.1523/JNEUROSCI.22-18-07913.2002
DP  - 2002 Sep 15
TA  - The Journal of Neuroscience
PG  - 7913--7922
VI  - 22
IP  - 18
4099  - http://www.jneurosci.org/content/22/18/7913.short
4100  - http://www.jneurosci.org/content/22/18/7913.full
SO  - J. Neurosci.2002 Sep 15; 22
AB  - Modulation of voltage-gated potassium (Kv) channels by protein phosphorylation plays an essential role in the regulation of the membrane properties of cells. Protein–protein binding domains, such as Src homology 3 (SH3) domains, direct ion channel modulation by coupling the channels with intracellular signaling enzymes. The conventional view is that protein kinase binding to ion channels leads to modulation by bringing the channel substrate into physical proximity to the enzyme, thereby fostering covalent modification of the channel. The SH3 domain binding-dependent functional suppression of Kv1.5 currents by Src family protein tyrosine kinases (PTKs) is considered a canonical example of this type of mechanism. In the present study we address whether the SH3-dependent binding of Src family PTKs toShaker family Kvs mediates modulatory events that are independent of and/or dependent on Src-catalyzed tyrosine phosphorylation of the channel. We find that Src binding and tyrosine phosphorylation are each able to modulate Kv1 family macroscopic channel currents independently. SH3-dependent binding of Src leads to the suppression of both Kv1.5 and Kv1.4 (modified to contain proline-rich SH3 domain binding sites) macroscopic currents even in the absence of Src-catalyzed tyrosine phosphorylation, whereas binding-independent tyrosine phosphorylation by Src leads to the suppression of Kv1.5 macroscopic currents and the modulation of Kv1.4 inactivation kinetics.