Phosphatidylinositol (4,5)-bisphosphate regulation of N-methyl-D-aspartate receptor channels in cortical neurons.
نویسندگان
چکیده
The membrane phospholipid phosphatidylinositol (4,5)-bisphosphate (PIP(2)) has been implicated in the regulation of several ion channels and transporters. In this study, we examined the impact of PIP(2) on N-methyl-D-aspartate receptors (NMDARs) in cortical neurons. Blocking PIP(2) synthesis by inhibiting phosphoinositide-4 kinase, or stimulating PIP(2) hydrolysis via activation of phospholipase C (PLC), or blocking PIP(2) function with an antibody caused a significant reduction of NMDAR-mediated currents. On the other hand, inhibition of PLC or application of PIP(2) caused an enhancement of NMDAR currents. These electrophysiological effects were accompanied by changes in NMDAR surface clusters induced by agents that manipulate PIP(2) levels. The PIP(2) regulation of NMDAR currents was abolished by the dynamin inhibitory peptide, which blocks receptor internalization. Agents perturbing actin stability prevented PIP(2) regulation of NMDAR currents, suggesting the actin-dependence of this effect of PIP(2). Cofilin, a major actin depolymerizing factor, which has a common binding sequence for actin and PIP(2), was required for PIP(2) regulation of NMDAR currents. It is noteworthy that the PIP(2) regulation of NMDAR channels was impaired in a transgenic mouse model of Alzheimer's disease, probably because of the amyloid-beta disruption of PIP(2) metabolism. Taken together, our data suggest that continuous synthesis of PIP(2) at the membrane might be important for the maintenance of NMDARs at the cell surface. When PIP(2) is lost, cofilin is released from the PIP(2) complex and is rendered free to depolymerize actin. With the actin cytoskeleton no longer intact, NMDARs are internalized via a dynamin/clathrin-dependent mechanism, leading to reduced NMDAR currents.
منابع مشابه
Phosphatidylinositol-4,5-Bisphosphate and -Actinin: Two-Component Hinge for the NMDA Receptor
متن کامل
NMDA Receptor-Mediated PIP5K Activation to Produce PI(4,5)P2 Is Essential for AMPA Receptor Endocytosis during LTD
NMDA receptor activation leads to clathrin-dependent endocytosis of postsynaptic AMPA receptors. Although this process controls long-term depression (LTD) induction in the hippocampus, how it is regulated by neuronal activities is not completely clear. Here, we show that Ca²⁺ influx through the NMDA receptor activates calcineurin and protein phosphatase 1 to dephosphorylate phosphatidylinositol...
متن کاملInteraction of aquaporin 4 and N-methyl-D-aspartate NMDA receptor 1 in traumatic brain injury of rats
Objective(s): -methyl-D-aspartate NMDA receptor (NMDAR) and aquaporin 4 (AQP4) are involved in the molecular cascade of edema after traumatic brain injury (TBI) and are potential targets of studies in pharmacology and medicine. However, their association and interactions are still unknown.Materials and Methods: We established a rat TBI model in this study. The cellular distribution patterns of ...
متن کاملPresynaptic inhibition via a phospholipase C- and phosphatidylinositol bisphosphate-dependent regulation of neuronal Ca2+ channels.
Presynaptic inhibition of transmitter release is commonly mediated by a direct interaction between G protein betagamma subunits and voltage-activated Ca2+ channels. To search for an alternative pathway, the mechanisms by which presynaptic bradykinin receptors mediate an inhibition of noradrenaline release from rat superior cervical ganglion neurons were investigated. The peptide reduced noradre...
متن کاملMicroinjection of NMDA Receptor Agents into the Central Nucleus of the Amygdale Alters Water Intake in Rats
Objective(s) The central nucleus of the amygdala (CeA) is a forebrain structure which is important in regulation of ingestive behavior and there is direct and circumstantial evidence to indicate that some circuits involved with feeding behavior include glutamatergic elements. The present study examined whether administration of NMA (N-Methyl-DL-aspartic acid) or MK801 into the CeA altered wate...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Molecular pharmacology
دوره 76 6 شماره
صفحات -
تاریخ انتشار 2009