A mechanism for combinatorial regulation of electrical activity: Potassiumchannel subunits capable of functioning as Src homology 3-dependent adaptors

It is an open question how ion channel subunits that lack protein-protein b inding motifs become targeted and covalently modified by cellular signaling enzymes. Here, we show that Src-family protein tyrosine kinases (PTKs) bin d to heteromultimeric: Shaker-family voltage-gated potassium (Kv) channels by interactions between the Src homology 3 (SH3) domain and the proline-ric h SH3 domain ligand sequence in the Shaker-family subunit Kv1.5. Once bound to Kv1.5, Src-family PTKs phosphorylate adjacent subunits in the Kv channe l heteromultimer that lack proline-rich SH3 domain ligand sequences. This S H3-dependent tyrosine phosphorylation contributes to significant suppressio n of voltage-evoked currents flowing through the heteromultimeric channel. These results demonstrate that Kv1.5 subunits function as SH3-dependent ada ptor proteins that marshal Src-family kinases to heteromultimeric potassium channel signaling complexes, and thereby confer functional sensitivity upo n coassembled channel subunits that are themselves not bound directly to Sr c-family kinases by allowing their phosphorylation. This is a mechanism for information transfer between subunits in heteromultimeric ion channels tha t is likely to underlie the generation of combinatorial signaling diversity in the control of cellular electrical excitability.