Stargazin and γ4 slow the channel opening and closing rates of GluA4 AMPA receptors

• Published in: Scientific reports 2019-07, Vol.9 (1), p.9570-10, Article 9570
• Main Authors: Pierce, Vincen D., Niu, Li
• Format: Article
• Language: English
• Subjects: 631/57; 631/57/2272/1590; 9/74; Alzheimer's disease; CACNG2 protein; Calcium channels (voltage-gated); Calcium Channels - genetics; Calcium Channels - metabolism; Cell Line; Channel opening; Dose-Response Relationship, Drug; Gene Expression; Glutamic Acid - metabolism; Glutamic Acid - pharmacology; Humanities and Social Sciences; Humans; Hypotheses; Ion Channel Gating - drug effects; Lasers; multidisciplinary; Open channels; Photolysis; Polyamines; Proteins; Receptor mechanisms; Receptors, AMPA - genetics; Receptors, AMPA - metabolism; Regulatory proteins; Science; Science (multidisciplinary); α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-45870-0

As auxiliary subunits, transmembrane AMPA receptor regulatory proteins (TARPs) are known to enhance macroscopic current amplitude and alter kinetic properties of AMPA receptors on slow time scale, such as desensitization rate. Whether TARPs affect the rate of AMPA channel opening and closing, however, remains elusive. Using a laser-pulse photolysis technique, we investigated the effect of γ-2 (stargazin, a type 1a TARP) and γ-4 (a type 1b TARP) on the channel-opening and channel-closing rate constants (i.e., k op and k cl ) of GluA4 homomeric channels. We found both TARPs slow the k op and k cl by 4-fold and 3-fold, respectively, without appreciable change of channel-opening probability, as compared with GluA4 channel alone. On the other hand, γ-4 has a stronger effect on slowing the channel desensitization rate than γ-2; yet, γ-2 causes a much more pronounced left shift of the dose-response relationship by increasing its affinity towards glutamate than γ-4. Our study shows that on the faster time scale, the major impact of TARP association with GluA4 is to lengthen the lifetime of the open channel, which is slow to form, to allow a larger charge transfer through the open channel that closes more slowly, without appreciable change of channel opening probability.