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The tetramerization domain potentiates Kv4 channel function by suppressing
closed-state inactivation
#MMPMID25185545
Tang YQ
; Zhou JH
; Yang F
; Zheng J
; Wang K
Biophys J
2014[Sep]; 107
(5
): 1090-1104
PMID25185545
show ga
A-type Kv4 potassium channels undergo a conformational change toward a
nonconductive state at negative membrane potentials, a dynamic process known as
pre-open closed states or closed-state inactivation (CSI). CSI causes inhibition
of channel activity without the prerequisite of channel opening, thus providing a
dynamic regulation of neuronal excitability, dendritic signal integration, and
synaptic plasticity at resting. However, the structural determinants underlying
Kv4 CSI remain largely unknown. We recently showed that the auxiliary KChIP4a
subunit contains an N-terminal Kv4 inhibitory domain (KID) that directly
interacts with Kv4.3 channels to enhance CSI. In this study, we utilized the
KChIP4a KID to probe key structural elements underlying Kv4 CSI. Using
fluorescence resonance energy transfer two-hybrid mapping and bimolecular
fluorescence complementation-based screening combined with electrophysiology, we
identified the intracellular tetramerization (T1) domain that functions to
suppress CSI and serves as a receptor for the binding of KID. Disrupting the
Kv4.3 T1-T1 interaction interface by mutating C110A within the C3H1 motif of T1
domain facilitated CSI and ablated the KID-mediated enhancement of CSI.
Furthermore, replacing the Kv4.3 T1 domain with the T1 domain from Kv1.4 (without
the C3H1 motif) or Kv2.1 (with the C3H1 motif) resulted in channels functioning
with enhanced or suppressed CSI, respectively. Taken together, our findings
reveal a novel (to our knowledge) role of the T1 domain in suppressing Kv4 CSI,
and that KChIP4a KID directly interacts with the T1 domain to facilitate Kv4.3
CSI, thus leading to inhibition of channel function.
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