Figure 3.

Multiple upstream signaling pathways function in concert to fine-tune the properties of I_A. (A) Extracellular-regulated kinase (ERK)– and protein kinase A (PKA)–mediated phosphorylation of Kv4.2 is downstream of the activation of the metabotropic glutamate receptor 5 (mGluR5) and decreases I_A densities (Hammond and others 2008; Hu and others 2003; Hu and others 2007; Yuan and others 2002). (B) Interaction of Kv4.2 with the A-kinase anchoring protein (AKAP) mediates the anchoring of PKA and decreases Kv4.2 surface expression (Lin and others 2011). Neuronal activity redistributes Kv4.2 from spines to dendritic shafts and soma through clathrin-mediated endocytosis and requires N-methyl-d-aspartate (NMDA) receptor activation and Ca²⁺ influx (Kim and others 2007). (C) Ca²⁺/calmodulin-dependent kinase II (CaMKII)–dependent phosphorylation of Kv4.2 (Shal in Drosophila) and increased I_A density (Ping and Tsunoda 2012; Varga and others 2004). Activation of α7 nicotinic acetylcholine receptors (nAChR) and increased Ca²⁺ influx results in downstream CaMKII-dependent phosphorylation of Kv4.2 and in increases in I_A densities.