MEMBRANE TRAFFICKING AND CHANNEL ABUNDANCE

University Of California San Francisco, San Francisco CA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (Provided by Applicant): For signaling to proceed normally in the nervous system, there has to be the right number of the right type of ion channels and transmitter receptors on the neuronal membrane. What kind of quality control machinery can ensure the proper assembly of these membrane protein complexes? How does a cell control the number of channels and receptors on its cell membrane? We have found a novel quality control mechanism that curtails the trafficking of inadequately assembled membrane protein complexes from the endoplasmic reticulum (ER) to the cell membrane. This ensures surface expression of fully assembled ATP-sensitive potassium (K-ATP channels with four Kir6.2 and four SUR subunits, and of properly assembled, heterodimeric GABA-B receptors that can functionally couple to the G protein-activated inwardly rectifying potassium (GIRK or Kir3) channels. The ER retention/retrieval signals in the K-ATP channels also limit the number of these channels on the cell surface. How general might be the use of ER retention/retrieval in the quality control of membrane protein complexes? Does the cell regulate other steps of membrane trafficking to control the number and type of ion channels and transmitter receptors? We have developed new methods to test the hypothesis that the numbers of different potassium channels are subjected to different membrane trafficking regulations. The examples to be used in our study are potassium channels that mediate slow synaptic potentials, control neuronal excitability, and potentially protect central neurons under stress. Mutations of potassium channel proteins are known to cause ataxia, epilepsy, deafness, arrhythmia, hypertension, and unchecked insulin release leading to hypoglycemia. Indeed, human epilepsy could result from mutations that reduce the M-type potassium channel activity by only 25 percent. And some of the disease-causing mutations alter the amount of functional potassium channels on the cell membrane. Our goal is to achieve better understanding as to how membrane trafficking regulates channel number and type. This may help us appreciate in the long run how regulation of membrane trafficking might contribute to synaptic plasticity, and whether malfunctions of this process contribute to mental and neurological diseases.