PIP3-Phldb2 is crucial for LTP regulating synaptic NMDA and AMPA receptor density and PSD95 turnover

Abstract

The essential involvement of phosphoinositides in synaptic plasticity is well-established, but incomplete knowledge of the downstream molecular entities prevents us from understanding their signalling cascades completely. Here, we determined that Phldb2, of which pleckstrin-homology domain is highly sensitive to PIP3, functions as a phosphoinositide-signalling mediator for synaptic plasticity. BDNF application caused Phldb2 recruitment toward postsynaptic membrane in dendritic spines, whereas PI3K inhibition resulted in its reduced accumulation. Phldb2 bound to postsynaptic scaffolding molecule PSD-95 and was crucial for localization and turnover of PSD-95 in the spine. Phldb2 also bound to GluA1 and GluA2. Phldb2 was indispensable for the interaction between NMDA receptors and CaMKII, and the synaptic density of AMPA receptors. Therefore, PIP3-responsive Phldb2 is pivotal for induction and maintenance of LTP. Memory formation was impaired in our Phldb2−/− mice.

Human cortical expansion involves diversification and specialization of supragranular intratelencephalic-projecting neurons

“…COBLL1 is a morphogenesis-associated gene that has been shown to promote dendrite branching and the formation of actin filament membrane ruffles 45 . Similarly, PHLDB2 localizes to dendritic spines of hippocampal neurons where it plays an important role in regulation of long-term potentiation by affecting the density of glutamate receptors, and knockout of this gene impairs the formation of memories in mice 46 . KCNK2 , which shows relatively selective expression in COL22A1 neurons, is a potassium channel, which can convert between voltage-insensitive potassium leak current and voltage-dependent outward rectifying current depending on phosphorylation 47 , and knockdown of this gene in mice impairs the migration of late-born neurons destined to become glutamatergic neurons in L2/3 48 .…”

Muscarinic Acetylcholine Receptor M5 Involved in Spermatogenesis through the Modification of Cell-Cell Junctions

“…7b). One of the genes, Phldb2, not only plays an important role in AChR aggregation in the postsynaptic membrane (Xie et al, 2019), but it is also involved in cell adhesion formation and extracellular matrix formation (Lim et al, 2016;Stehbens et al, 2014). Phldb2 interacts with CLASP and lamins during its involvement in focal adhesion and extracellular matrix turnover (Fig.…”

“…Phldb2 is a PH domain-containing protein that is highly sensitive to phosphatidylinositol 3,4,5triphosphate (PIP3) as well as PIP2 (Xie et al, 2019). Phldb2 plays important roles in AChR aggregation in the postsynaptic membrane (Xie et al, 2019).…”

“…Phldb2 is a PH domain-containing protein that is highly sensitive to phosphatidylinositol 3,4,5triphosphate (PIP3) as well as PIP2 (Xie et al, 2019). Phldb2 plays important roles in AChR aggregation in the postsynaptic membrane (Xie et al, 2019). Moreover, Phldb2 can associate with CLIP-associating proteins (CLASPs), Prickle 1, and Liprin α1 to be involved in focal adhesion disassembly and cell polarization and migration (Lim et al, 2016;Astro et al, 2014;Lansbergen et al, 2006).…”

“…In the current study, we report that gene knockdown of M5 disrupted mouse spermatogenesis and damaged the actin-based cytoskeleton and many types of junction proteins in both Sertoli cells (TM4) and germ cells (C18-4); however, knockdown of M1 or M3 had little effect on spermatogenesis even though there are many similarities between mAChRs M1, M3, and M5. Phldb2 (pleckstrin homology-like domain, family B, member 2, alternatively called LL5β) not only plays important roles in acetylcholine receptor (AChR) aggregation in the postsynaptic membrane, it is also involved in cell adhesion formation and extracellular matrix formation (Xie et al, 2019;Lim et al, 2016;Stehbens et al, 2014). Knockdown of M5 decreased PHLDB2 expression in both germ cells and Sertoli cells.…”