Phosphatidylinositol 4,5-bisphosphate (PIP2) is an important cellular effector whose functions include the regulation of ion channels and membrane trafficking. Aberrant PIP 2 metabolism has also been implicated in a variety of human disease states, e.g., cancer and diabetes. Here we report that familial Alzheimer's disease (FAD)-associated presenilin mutations cause an imbalance in PIP 2 metabolism. We find that the transient receptor potential melastatin 7 (TRPM7)-associated Mg 2؉ -inhibited cation (MIC) channel underlies ion channel dysfunction in presenilin FAD mutant cells, and the observed channel deficits are restored by the addition of PIP 2, a known regulator of the MIC/TRPM7 channel. Lipid analyses show that PIP 2 turnover is selectively affected in FAD mutant presenilin cells. We also find that modulation of cellular PIP 2 closely correlates with 42-residue amyloid -peptide (A42) levels. Our data suggest that PIP 2 imbalance may contribute to Alzheimer's disease pathogenesis by affecting multiple cellular pathways, such as the generation of toxic A42 as well as the activity of the MIC/TRPM7 channel, which has been linked to other neurodegenerative conditions. Thus, our study suggests that brain-specific modulation of PIP 2 may offer a therapeutic approach in Alzheimer's disease.-amyloid precursor protein ͉ channel ͉ secretase ͉ transient receptor potential melastatin 7 (TRPM7) ͉ capacitative calcium entry
cDNAs encoding large-conductance Ca 2+ -activated K + channel a-subunit (rSlo) were obtained from rat brain. From the DNA sequence of multiple rslo clones, we identified a specific sequence variation of 81 nucleotides, which is either absent from or present at the N-terminal region of a putative Ca 2+ -sensing domain of the channel. Transcripts containing such variations were detected in different ratios from several brain regions, and their functional significance was further examined. When heterologously expressed in Xenopus oocytes, both rSlo variants, named rSlo 0 and rSlo 27 , generated Ca 2+ -activated and voltage-activated K + currents characteristic of neuronal large-conductance Ca 2+ -activated K + (BK Ca ) channels. Single-channel recordings of the two channels showed almost identical permeation characteristics and steady-state gating behavior. Noticeable differences between rSlo 0 and rSlo 27 were revealed when the macroscopic currents were measured at various voltages and intracellular Ca 2+ concentrations. rSlo 27 activated was more rapidly than rSlo 0 in the presence of the same voltage stimulus, and the differences in these activation kinetics were dependent on the concentration of intracellular Ca 2+ . Despite their similar apparent affinities for Ca 2+ , rSlo 0 and rSlo 27 showed significant differences in their co-operative gating behavior. The Hill coefficient for intracellular Ca 2 was estimated to be about 3.7 for rSlo 27 regardless of the membrane voltage, and that for rSlo 0 was reduced from about 5 to 2 as the membrane voltage changed from 40 to 140 mV. As activation of BK Ca channels is involved in rapid hyperpolarization of action potentials, the differential processing of rslo transcripts, and the generation of channels with different activation kinetics and Ca 2+ cooperativity may be a mechanism for tuning the excitability of neurons in different brain regions.
Information on the neurons and axons that express the mechanosensitive channel Piezo1 and its expression in axons innervating the dental pulp may help understand the nature of the Piezo1-mediated mechanosensation and the underlying mechanism of dentin sensitivity elicited by mechanical stimuli. For this, we here investigated the neurochemical properties of the neurons in the rat trigeminal ganglion (TG) and their axons in its sensory root that express Piezo1 and the expression of Piezo1 in the rat and human dental pulp by light and electron microscopic immunohistochemistry and quantitative analysis. Piezo1 was expressed mainly in medium-sized and large TG neurons. Piezo1-immunopositive (+) neurons frequently coexpressed the marker for neurons with myelinated axons, NF200, but rarely the markers for neurons with unmyelinated axons, CGRP or IB4. In the sensory root of TG, Piezo1 was expressed primarily in small myelinated axons (Aδ, 60.2%) but also in large myelinated (Aβ, 24.3%) and unmyelinated (C, 15.5%) axons. In the human dental pulp, Piezo1 was expressed in numerous NF200+ axons, which formed a network in the peripheral pulp and often “ascended” toward the dentin. Most Piezo1+ myelinated axons in the radicular pulp became unmyelinated in the peripheral pulp, where Piezo1 immunoreaction product was associated with the axonal plasma membrane, suggesting a functional role of Piezo1 in the peripheral pulp. These findings suggest that Piezo1 is involved primarily in mediating the acute pain elicited by high-threshold mechanical stimuli, and that the Piezo1-mediated dental mechanotransduction occurs primarily in the axons in the peripheral pulp.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.