Voltage-sensitive neuronal Kv1 channels composed of four α subunits and four associated auxiliary β subunits control neuronal excitability and neurotransmission. Limited information exists on the combinations of α subunit isoforms (i.e. Kv1.1–1.6) or their positions in the oligomers, and how these affect sensitivity to blockers. It is known that TEA (tetraethylammonium) inhibits Kv1.1 channels largely due to binding a critical tyrosine (Tyr379) in the pore, whereas Val381 at the equivalent location in Kv1.2 makes it insensitive. With the eventual aim of developing blockers for therapeutic purposes, Kv1.1 and 1.2 α subunit genes were concatenated to form combinations representing those in central neurons, followed by surface expression in HEK (human embryonic kidney)-293 cells as single-chain functional proteins. Patch-clamp recordings demonstrated the influences of the ratios and positioning of these α subunits on the biophysical and pharmacological properties of oligomeric K+ channels. Raising the ratio of Kv1.1 to Kv1.2 in Kv1.2-1.2-1.1-1.2 led to the resultant channels being more sensitive to TEA and also affected their biophysical parameters. Moreover, mutagenesis of one or more residues in the first Kv1.2 to resemble those in Kv1.1 increased TEA sensitivity only when it is adjacent to a Kv1.1 subunit, whereas placing a non-interactive subunit between these two diminished susceptibility. The findings of the present study support the possibility of α subunits being precisely arranged in Kv1 channels, rather than being randomly assembled. This is important in designing drugs with abilities to inhibit particular oligomeric Kv1 subtypes, with the goal of elevating neuronal excitability and improving neurotransmission in certain diseases.
Skip Nav Destination
Close
Article navigation
August 2013
- Cover Image
- PDF Icon PDF LinkFront Matter
- PDF Icon PDF LinkTable of Contents
- PDF Icon PDF LinkEditorial Board
Research Article|
July 26 2013
Pharmacological characteristics of Kv1.1- and Kv1.2-containing channels are influenced by the stoichiometry and positioning of their α subunits
Ahmed Al-Sabi
;
Ahmed Al-Sabi
1
1International Centre for Neurotherapeutics, Dublin City University, Glasnevin, Dublin 9, Ireland
Search for other works by this author on:
Seshu Kumar Kaza
;
Seshu Kumar Kaza
1
1International Centre for Neurotherapeutics, Dublin City University, Glasnevin, Dublin 9, Ireland
Search for other works by this author on:
J. Oliver Dolly
;
J. Oliver Dolly
2
1International Centre for Neurotherapeutics, Dublin City University, Glasnevin, Dublin 9, Ireland
2To whom correspondence should be addressed (email oliver.dolly@dcu.ie).
Search for other works by this author on:
Jiafu Wang
Jiafu Wang
1International Centre for Neurotherapeutics, Dublin City University, Glasnevin, Dublin 9, Ireland
Search for other works by this author on:
Biochem J (2013) 454 (1): 101–108.
Article history
Received:
March 05 2013
Revision Received:
May 28 2013
Accepted:
May 31 2013
Accepted Manuscript online:
May 31 2013
Citation
Ahmed Al-Sabi, Seshu Kumar Kaza, J. Oliver Dolly, Jiafu Wang; Pharmacological characteristics of Kv1.1- and Kv1.2-containing channels are influenced by the stoichiometry and positioning of their α subunits. Biochem J 15 August 2013; 454 (1): 101–108. doi: https://doi.org/10.1042/BJ20130297
Download citation file:
Close
Sign in
Don't already have an account? Register
Sign in to your personal account
You could not be signed in. Please check your email address / username and password and try again.
Biochemical Society Member Sign in
Sign InSign in via your Institution
Sign in via your InstitutionGet Access To This Article
Cited By
Related Articles
Modulation of Kv2.1 channel gating and TEA sensitivity by distinct domains of SNAP-25
Biochem J (May,2006)
Voltage-dependent gating properties of the channel formed by E. coli hemolysin in planar lipid membranes
Biosci Rep (August,1989)
The C-terminal basic residues contribute to the chemical- and voltage-dependent activation of TRPA1
Biochem J (December,2010)
Impact of subunit positioning on GABA A receptor function
Biochem Soc Trans (October,2006)