Ion Channel Regulation by Protein Palmitoylation

Michael J. Shipston

doi:10.1074/jbc.r110.210005

Abstract

Protein S-palmitoylation, the reversible thioester linkage of a 16-carbon palmitate lipid to an intracellular cysteine residue, is rapidly emerging as a fundamental, dynamic, and widespread post-translational mechanism to control the properties and function of ligand- and voltage-gated ion channels. Palmitoylation controls multiple stages in the ion channel life cycle, from maturation to trafficking and regulation. An emerging concept is that palmitoylation is an important determinant of channel regulation by other signaling pathways. The elucidation of enzymes controlling palmitoylation and developments in proteomics tools now promise to revolutionize our understanding of this fundamental post-translational mechanism in regulating ion channel physiology.

Highlights

Protein S-palmitoylation, the most common form of protein S-acylation identified over 30 years ago [1], involves the addition of a 16-carbon chain palmitic acid, via a hydroxylamine-sensitive thioester linkage, to intracellular cysteine residues
The last 5 years have seen a major resurgence in the protein palmitoylation field due, in large part, to the development of new proteomics tools and characterization of the major palmitoylating enzymes
Mechanistic insight into the target selectivity of zDHHCs will allow us to understand the coordinated regulation of ion channels by palmitoylation signaling cascades and to decipher how distinct domains on the same channel may be differentially regulated by palmitoylation

Summary

Ion Channel Regulation by Protein Palmitoylation*

From the Centre for Integrative Physiology, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh EH8 9XD, Scotland, United Kingdom. Protein S-palmitoylation, the reversible thioester linkage of a 16-carbon palmitate lipid to an intracellular cysteine residue, is rapidly emerging as a fundamental, dynamic, and widespread post-translational mechanism to control the properties and function of ligand- and voltage-gated ion channels. Palmitoylation of a cluster of C-terminal cysteines in the pore-forming NR2A subunit of NMDA receptors [22] and a cysteine residue juxtaposed to the M2 membrane domain in the GluR1 subunit of AMPA receptors [23] controls Golgi retention of the respective channel, whereas palmitoylation of the intracellular Nterminal S0-S1 loop of large conductance calcium- and voltage-activated potassium (BK) channels modulates but is not essential for cell-surface delivery [24]. Cysteine residues often form disulfide cross-bridges, or their free sulfhydryl groups are targets for both redox as well as S-nitrosylation pathways, all of which are important ion channel regulators

Location of Palmitoylated Cysteine Is Important for Function

Identification of Palmitoyl Acyltransferases and Acyl Thioesterases

Other channels identified in mammalian palmitoylome screens

Biochemical Identification of Protein Palmitoylation

Genetic Manipulation of zDHHCs and Thioesterases

Pharmacological Manipulation of Palmitoylation

Conclusions and Perspectives

Methods