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Molecular Pharmacology Fast Forward
First published on November 17, 2005; DOI: 10.1124/mol.105.020727

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Received for publication November 10, 2005.
Revised November 10, 2005.
Accepted for publication November 17, 2005.

PRETTY SUBUNITS ALL IN A ROW: USING CONCATENATED SUBUNIT CONSTRUCTS TO FORCE THE EXPRESSION OF RECEPTORS WITH DEFINED SUBUNIT STOICHIOMETRY AND SPATIAL ARRANGEMENT (Relates to Article by Groot-Kormelink, et al. FastForward 3 November 2005)

Michael M. White 1*

1 Drexel University College of Medicine, MS 488

* Address correspondence to: E-mail: mikewhite{at}drexel.edu

Abstract

The members of the cys-loop ligand-gated ion channel gene family play a major role in fast synaptic transmission, and these receptors represent an important class of targets for therapeutic agents. Each member of this gene family is a pentameric complex containing one or more different subunits, and a large number of subunits for each member have been identified. This large number of subunits could give rise to a bewildering array of possible subunit compositions and spatial arrangements within a single complex, not all of which may occur in vivo. Heterologous expression systems have been used to create specific combinations of individual subunits in order to mimic naturally-occurring receptors. However, this approach is not without its problems. In this issue of Molecular Pharmacology, Groot-Kormelink et al. (page @@@) describe a method for constructing concatameric receptors, in which five individual subunits are arranged in a predetermined order connected by a flexible linker. Expression of this construct results in the formation of receptors with a unique, predefined subunit stoichiometry and subunit arrangement within the receptor complex. Receptors formed from this construct are fully functional and have properties essentially identical to those formed from individual subunits. The application of this very general approach to other members of the LGIC family should markedly enhance our ability to understand how subunit composition influences receptor function, as well provide a means for the expression of receptors of predefined subunit composition and arrangement as tools for the development of novel selective pharmacological and therapeutic agents.


Key words: Nicotinic cholinergic, GABAA, GABAC, Glycine, Serotonin, Func. analysis receptor/ion channel mutants


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J. T. Sack, O. Shamotienko, and J. O. Dolly
How to Validate a Heteromeric Ion Channel Drug Target: Assessing Proper Expression of Concatenated Subunits
J. Gen. Physiol., May 1, 2008; 131(5): 415 - 420.
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