Multiprotein assembly of Kv4.2, KChIP3 and DPP10 produces ternary channel complexes with I_SA‐like properties

Abstract

∼18-26 ms), closely matching that of native I SA and significantly faster than the recovery of Kv4.2 + KChIP3 or Kv4.2 + DPP10 channels. For comparison, identical triple coexpression experiments were performed using DPP6 variants. While most results are similar, the Kv4.2 + KChIP3 + DPP6 channels exhibit inactivation that slows with increasing membrane potential, resulting in inactivation slower than that of Kv4.2 + KChIP3 + DPP10 channels at positive voltages. In conclusion, the native neuronal subthreshold A-type channel is probably a macromolecular complex formed from Kv4 and a combination of both KChIP and DPL proteins, with the precise composition of channel α and auxiliary subunits underlying tissue and regional variability in I SA properties.

Multiple Kv Channel-interacting Proteins Contain an N-terminal Transmembrane Domain That Regulates Kv4 Channel Trafficking and Gating

“…In contrast, Kv4.2 inactivation accelerates with increasing voltage (8,25). This inverse voltage dependence appears to be characteristic of the Kv4 closed state inactivation mechanism, which becomes increasingly less effective with increasing depolarization (25)(26)(27). This result suggests that the primary effect of the KISD is to slow the kinetics of the closed state inactivation pathway, probably via slowed channel closing (7), after the KChIP core sequesters the N-type-like inactivation mechanism.…”

“…In the presence of KChIP4a, KChIP2x, KChIP3x, and KChIP3a, Kv4.2 inactivates with an inverse voltage dependence, where increases in voltage result in decreases in inactivation rate. In contrast, Kv4.2 inactivation accelerates with increasing voltage (8,25). This inverse voltage dependence appears to be characteristic of the Kv4 closed state inactivation mechanism, which becomes increasingly less effective with increasing depolarization (25)(26)(27).…”

“…Multiple KChIP Isoforms Have KISDs-The major focus for molecular studies on neuronal I SA has been on identifying auxiliary subunits that produce fast rapid activation and inactivation gating (25,32,33), making KChIP4a a curiosity among the I SA subunits. Here we show that KChIP4a is no lone oddball but rather is one member of a group of KChlPs that modify I SA channel expression and functional properties by providing an additional regulatory transmembrane domain that modifies the functional properties of the transmembrane pore gates.…”

Kv4.3 is not required for the generation of functional Ito,f channels in adult mouse ventricles

“…Interestingly, a novel Kv4 accessory subunit, DPP6, a member of the diaminopeptidyl transferase (DPP) family of proteins was identified in brain, and shown to regulate the expression and the properties of Kv4 channels [30,31]. Although at least one additional member (DPP10) of this family has been identified as a Kv4 channel regulatory subunit [32], neither DPP6 nor DPP10 has been shown to be expressed in the myocardium. Nevertheless, there may be other cardiac specific regulators of Kv4 encoded I to,f channels.…”

IA Channels Encoded by Kv1.4 and Kv4.2 Regulate Neuronal Firing in the Suprachiasmatic Nucleus and Circadian Rhythms in Locomotor Activity

“…A-type (I A ) voltage-gated K ϩ (Kv) channels activate and inactivate rapidly on membrane depolarization and, on hyperpolarization, recover rapidly from inactivation (Connor and Stevens, 1971a;Birnbaum et al, 2004;Jerng et al, 2005;Covarrubias et al, 2008). In many neurons, these properties impact repetitive firing rates (Connor and Stevens, 1971b;Kang et al, 2000;Kim et al, 2005;Yuan et al, 2005;Khaliq and Bean, 2008).…”