A mutation in the extracellular domain of the alpha 7 nAChR reduces calcium permeability

作者：Colon Saez Jose O; Yakel Jerrel L^*

来源：Pflugers Archiv-European Journal of Physiology, 2014, 466(8): 1571-1579.

DOI：10.1007/s00424-013-1385-y

• Alpha 7 nAChR
• Calcium permeability
• Extracellular domain
• Mutagenesis

The alpha 7 neuronal nicotinic acetylcholine receptor (nAChR) displays the highest calcium permeability among the different subtypes of nAChRs expressed in the mammalian brain and can impact cellular events including neurotransmitter release, second messenger cascades, cell survival, and apoptosis. The selectivity for cations in nAChRs is thought to be achieved in part by anionic residues which are located on either side of the channel mouth and increase relative cationic concentration. Mutagenesis studies have improved our understanding of the role of the second transmembrane domain and the intracellular loop of the channel in ion selectivity. However, little is known about the influence that the extracellular domain (ECD) plays in ion permeation. In the alpha 7 nAChR, it has been found that the ECD contains a ring of ten aspartates (two per subunit) that is believed to face the lumen of the pore and could attract cations for permeation. Using mutagenesis and a combination of electrophysiology and imaging techniques, we tested the possible involvement of these aspartate residues in the calcium permeability of the rat alpha 7 nAChR. We found that one of these residues (the aspartate at position 44) appears to be essential since mutating it to alanine resulted in a decrease in amplitude for both whole cell and single-channel responses and in the complete disappearance of detectable calcium changes in most cells, which indicates that the ECD of the alpha 7 nAChR plays a key role in calcium permeation.

• 出版日期2014-8