The A‐Type Potassium Channel Kv4.2 Is a Substrate for the Mitogen‐Activated Protein Kinase ERK

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Abstract
The mitogen‐activated protein kinase ERK has recentlybecome a focus of studies of synaptic plasticity and learning and memory. Dueto the prominent role of potassium channels in regulating the electricalproperties of membranes, modulation of these channels by ERK could play animportant role in mediating learning‐related synaptic plasticity in the CNS.Kv4.2 is a Shal‐type potassium channel that passes an A‐type current and islocalized to dendrites and cell bodies in the hippocampus. The sequence ofKv4.2 contains several consensus sites for ERK phosphorylation. In the presentstudies, we tested the hypothesis that Kv4.2 is an ERK substrate. Wedetermined that the Kv4.2 C‐terminal cytoplasmic domain is an effective ERK2substrate, and that it is phosphorylated at three sites: Thr602,Thr607, and Ser616. We used this information to developantibodies that recognize Kv4.2 phosphorylated by ERK2. One of ourphospho‐site‐selective antibodies was generated using a triply phosphorylatedpeptide as the antigen. We determined that this antibody recognizesERK‐phosphorylated Kv4.2 in COS‐7 cells transfected with Kv4.2 and nativeERK‐phosphorylated Kv4.2 in the rat hippocampus. These observations indicatethat Kv4.2 is a substrate for ERK in vitro and in vivo, and suggest that ERKmay regulate potassium‐channel function by direct phosphorylation of thepore‐forming α subunit.