Dougherty K

References (3)

Title : The dipeptidyl-aminopeptidase-like protein 6 is an integral voltage sensor-interacting beta-subunit of neuronal K(V)4.2 channels - Dougherty_2009_Channels.(Austin)_3_122
Author(s) : Dougherty K , Tu L , Deutsch C , Covarrubias M
Ref : Channels (Austin) , 3 :122 , 2009
Abstract : Auxiliary beta-subunits dictate the physiological properties of voltage-gated K(+) (K(V)) channels in excitable tissues. In many instances, however, the underlying mechanisms of action are poorly understood. The dipeptidyl-aminopeptidase-like protein 6 (DPP6) is a specific beta-subunit of neuronal K(V)4 channels, which may promote gating through interactions between the single transmembrane segment of DPP6 and the channel's voltage sensing domain (VSD). A combination of gating current measurements and protein biochemistry (in-vitro translation and co-immunoprecipitations) revealed preferential physical interaction between the isolated K(V)4.2-VSD and DPP6. Significantly weaker interactions were detected between DPP6 and K(V)1.3 channels or the K(V)4.2 pore domain. More efficient gating charge movement resulting from a direct interaction between DPP6 and the K(V)4.2-VSD is unique among the known actions of K(V) channel beta-subunits. This study shows that the modular VSD of a K(V) channel can be directly regulated by transmembrane protein-protein interactions involving an extrinsic beta-subunit. Understanding these interactions may shed light on the pathophysiology of recently identified human disorders associated with mutations affecting the dpp6 gene.
ESTHER : Dougherty_2009_Channels.(Austin)_3_122
PubMedSearch : Dougherty_2009_Channels.(Austin)_3_122
PubMedID: 19372736
Gene_locus related to this paper: human-DPP6

Title : The neuronal Kv4 channel complex - Covarrubias_2008_Neurochem.Res_33_1558
Author(s) : Covarrubias M , Bhattacharji A , De Santiago-Castillo JA , Dougherty K , Kaulin YA , Na-Phuket TR , Wang G
Ref : Neurochem Res , 33 :1558 , 2008
Abstract : Kv4 channel complexes mediate the neuronal somatodendritic A-type K(+) current (I(SA)), which plays pivotal roles in dendritic signal integration. These complexes are composed of pore-forming voltage-gated alpha-subunits (Shal/Kv4) and at least two classes of auxiliary beta-subunits: KChIPs (K(+)-Channel-Interacting-Proteins) and DPLPs (Dipeptidyl-Peptidase-Like-Proteins). Here, we review our investigations of Kv4 gating mechanisms and functional remodeling by specific auxiliary beta-subunits. Namely, we have concluded that: (1) the Kv4 channel complex employs novel alternative mechanisms of closed-state inactivation; (2) the intracellular Zn(2+) site in the T1 domain undergoes a conformational change tightly coupled to voltage-dependent gating and is targeted by nitrosative modulation; and (3) discrete and specific interactions mediate the effects of KChIPs and DPLPs on activation, inactivation and permeation of Kv4 channels. These studies are shedding new light on the molecular bases of I(SA) function and regulation.
ESTHER : Covarrubias_2008_Neurochem.Res_33_1558
PubMedSearch : Covarrubias_2008_Neurochem.Res_33_1558
PubMedID: 18357523

Title : A dipeptidyl aminopeptidase-like protein remodels gating charge dynamics in Kv4.2 channels - Dougherty_2006_J.Gen.Physiol_128_745
Author(s) : Dougherty K , Covarrubias M
Ref : Journal of General Physiology , 128 :745 , 2006
Abstract : Dipeptidyl aminopeptidase-like proteins (DPLPs) interact with Kv4 channels and thereby induce a profound remodeling of activation and inactivation gating. DPLPs are constitutive components of the neuronal Kv4 channel complex, and recent observations have suggested the critical functional role of the single transmembrane segment of these proteins (Zagha, E., A. Ozaita, S.Y. Chang, M.S. Nadal, U. Lin, M.J. Saganich, T. McCormack, K.O. Akinsanya, S.Y. Qi, and B. Rudy. 2005. J. Biol. Chem. 280:18853-18861). However, the underlying mechanism of action is unknown. We hypothesized that a unique interaction between the Kv4.2 channel and a DPLP found in brain (DPPX-S) may remodel the channel's voltage-sensing domain. To test this hypothesis, we implemented a robust experimental system to measure Kv4.2 gating currents and study gating charge dynamics in the absence and presence of DPPX-S. The results demonstrated that coexpression of Kv4.2 and DPPX-S causes a -26 mV parallel shift in the gating charge-voltage (Q-V) relationship. This shift is associated with faster outward movements of the gating charge over a broad range of relevant membrane potentials and accelerated gating charge return upon repolarization. In sharp contrast, DPPX-S had no effect on gating charge movements of the Shaker B Kv channel. We propose that DPPX-S destabilizes resting and intermediate states in the voltage-dependent activation pathway, which promotes the outward gating charge movement. The remodeling of gating charge dynamics may involve specific protein-protein interactions of the DPPX-S's transmembrane segment with the voltage-sensing and pore domains of the Kv4.2 channel. This mechanism may determine the characteristic fast operation of neuronal Kv4 channels in the subthreshold range of membrane potentials.
ESTHER : Dougherty_2006_J.Gen.Physiol_128_745
PubMedSearch : Dougherty_2006_J.Gen.Physiol_128_745
PubMedID: 17130523