Alzheimer's disease (AD) is characterized by amyloid-beta (Abeta) and tau deposition in brain. It has emerged that Abeta toxicity is tau dependent, although mechanistically this link remains unclear. Here, we show that tau, known as axonal protein, has a dendritic function in postsynaptic targeting of the Src kinase Fyn, a substrate of which is the NMDA receptor (NR). Missorting of tau in transgenic mice expressing truncated tau (Deltatau) and absence of tau in tau(-/-) mice both disrupt postsynaptic targeting of Fyn. This uncouples NR-mediated excitotoxicity and hence mitigates Abeta toxicity. Deltatau expression and tau deficiency prevent memory deficits and improve survival in Abeta-forming APP23 mice, a model of AD. These deficits are also fully rescued with a peptide that uncouples the Fyn-mediated interaction of NR and PSD-95 in vivo. Our findings suggest that this dendritic role of tau confers Abeta toxicity at the postsynapse with direct implications for pathogenesis and treatment of AD.

It is well known that iron (Fe) is trans- IntroductionSince its discovery, the mitochondrion has been known as an essential and dynamic component of cellular biochemistry. The complexity of the mitochondrion has been gradually revealed by the study of a variety of genetic diseases associated with its function. Thus far, it is clear that Fe plays a crucial role in many facets of mitochondrial metabolism and the consequences of disruption to these pathways are catastrophic. Therefore, it would seem clear that the mitochondrion, a site of dynamically active electron transport and redox activity, would possess sufficient measures for the safe trafficking and metabolism of Fe. However, until recently, knowledge of the Fe metabolism of the mitochondrion has been largely confined to the heme synthesis pathway (for review, see Ponka 1 ), and very little was understood concerning the trafficking and storage of Fe in this organelle.The recent discovery of a plethora of mitochondrial proteins believed to be involved in Fe metabolism has resulted in a marked increase of research in this field. Key proteins identified include frataxin, ATP-binding cassette protein B7 (ABCB7), and the more recently discovered mitochondrial ferritin. These discoveries have provided evidence to support the hypothesis that the mitochondrion is a distinct compartment of Fe metabolism. However, despite these new data, the Fe trafficking pathways within the mitochondrion remain unclear, and in this review we will attempt to analyze and integrate the most recent findings in this intriguing field. Iron transport, storage, and homeostatic regulationBefore discussing the most recent results regarding mitochondrial Fe metabolism, we will first provide a brief overview of the well-characterized molecular pathways of cellular Fe trafficking and utilization. Iron is transported within the serum bound to the Fe-binding protein, transferrin (Tf), 2-4 that binds to the transferrin receptor 1 (TfR1; Figure 1). The receptor binds 2 molecules of Fe-loaded Tf, 5 resulting in receptor-mediated endocytosis of the Tf-TfR1 complex (for reviews, see Morgan, 2 Richardson and Ponka, 3 and Hentze et al 4 ). A reduction in endosomal pH 2,3,6 mediates the release of Fe from Tf. 2,7 A protein known as the natural resistance-associated macrophage protein 2 (Nramp2) 8 was subsequently demonstrated to be the long sought-after exporter of Fe ϩ2 from endosomes. [9][10][11] This molecule is now known as divalent metal ion transporter 1 (DMT1) but has also been denoted as the divalent cation transporter 1 (DCT1) or solute carrier family 11a member 2 (Slc11a2).Within the cytosol, Fe can be stored in a large multimeric protein known as ferritin. 12 The storage of Fe in this molecule protects the cells from the damaging effects of free Fe and also keeps it sequestered in a bioavailable form. Since Fe is such an important but potentially toxic metal, its uptake, storage, and mobilization pathways are tightly regulated. This homeostatic control mechanism is largely controlled by RNA-bi...

⌬9 -Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most prevalent biologically active constituents of Cannabis sativa. THC is the prototypic cannabinoid CB1 receptor agonist and is psychoactive and analgesic. CBD is also analgesic, but it is not a CB1 receptor agonist. Low voltage-activated T-type calcium channels, encoded by the Ca V 3 gene family, regulate the excitability of many cells, including neurons involved in nociceptive processing. We examined the effects of THC and CBD on human Ca V 3 channels stably expressed in human embryonic kidney 293 cells and T-type channels in mouse sensory neurons using whole-cell, patch clamp recordings. At moderately hyperpolarized potentials, THC and CBD inhibited peak Ca V 3.1 and Ca V 3.2 currents with IC 50 values of ϳ1 M but were less potent on Ca V 3.3 channels. THC and CBD inhibited sensory neuron T-type channels by about 45% at 1 M. However, in recordings made from a holding potential of ؊70 mV, 100 nM THC or CBD inhibited more than 50% of the peak Ca V 3.1 current. THC and CBD produced a significant hyperpolarizing shift in the steady state inactivation potentials for each of the Ca V 3 channels, which accounts for inhibition of channel currents. Additionally, THC caused a modest hyperpolarizing shift in the activation of Ca V 3.1 and Ca V 3.2. THC but not CBD slowed Ca V 3.1 and Ca V 3.2 deactivation and inactivation kinetics. Thus, THC and CBD inhibit Ca V 3 channels at pharmacologically relevant concentrations. However, THC, but not CBD, may also increase the amount of calcium entry following T-type channel activation by stabilizing open states of the channel.Cannabis sativa has a long history of medicinal and social use (1). It is taken regularly by ϳ5-8% of the adults in developed countries (2, 3) and by up to 20% of those suffering neurological conditions such as multiple sclerosis, epilepsy, and chronic pain (4 -6). Since the isolation of the major psychologically active constituent of C. sativa, ⌬ 9 -tetrahydrocannabinol (THC) 4 (7), more than 60 other compounds with biological activity have been identified (8). These include cannabidiol (CBD) (9), the most abundant biologically active compound after THC in the plant. The widespread use of cannabis for self-medication and social purposes and the potential of its constituents as new therapeutic agents make it important that the molecular targets for THC and CBD are well defined.Most of the effects of THC are likely to occur through actions on G protein-coupled CB1 and CB2 cannabinoid receptors (10, 11) but CBD is an inverse agonist (CB2) or weak antagonist (CB1) at these receptors (12). When administered systemically, CB1 agonists cause a classic "tetrad" of behavioral effects in rodents: hypothermia, catalepsy, hypolocomotion, and antinociception (13). However, THC has non-CB receptor-mediated effects in animals including anti-nociceptive effects in the tail-flick assay of thermal nociception in CB1 receptor knock-out mice (14). Potential non-CB1/CB2 receptor sites of THC action (reviewed in Ref....

Sustained stimulation of G-protein coupled receptors (GPCRs) leads to rapid loss of receptor function (acute desensitization). For manyGPCRs including the -opioid receptor (MOR), an accepted mechanism for acute desensitization is through G-protein coupled receptor kinase (GRKs) mediated phosphorylation of the receptor, which facilitates the binding of ␤-arrestins (␤arrs) to the receptor and then promotes endocytosis. However, the mechanism(s) that mediate acute desensitization have not yet been well defined in native neurons. This study used whole-cell patch clamp recording of G-protein coupled inward-rectifying potassium (GIRK) currents to assay MOR function and identify mechanisms of acute MOR desensitization in locus ceruleus (LC) neurons. The rate and extent of MOR desensitization were unaffected by ␤arr-2 knock-out. Disruption of GRK2 function via inhibitory peptide introduced directly into neurons also failed to affect desensitization in wild type or ␤arr-2 knock-outs. Inhibition of ERK1/2 activation alone had little effect on acute desensitization. However, when both GRK2-␤arr-2 and ERK1/2 functions were disrupted simultaneously, desensitization of MOR was nearly abolished. Together, these results suggest that acute desensitization of MOR in native LC neurons is determined by at least two molecular pathways, one involving GRK2 and ␤arr-2, and a parallel pathway mediated by activated ERK1/2.

The large diversity of peptides from venomous creatures with high affinity for molecules involved in the development and maintenance of neuropathic pain has led to a surge in venom-derived analgesic research. Some members of the α-conotoxin family from Conus snails which specifically target subtypes of nicotinic acetylcholine receptors (nAChR) have been shown to be effective at reducing mechanical allodynia in neuropathic pain models. We sought to determine if three such peptides, Vc1.1, AuIB and MII were effective following intrathecal administration in a rat neuropathic pain model because they exhibit different affinities for the major putative pain relieving targets of α-conotoxins. Intrathecal administration of α-conotoxins, Vc1.1, AuIB and MII into neuropathic rats reduced mechanical allodynia for up to 6 hours without significant side effects. In vitro patch-clamp electrophysiology of primary afferent synaptic transmission revealed the mode of action of these toxins was not via a GABA B -dependant mechanism, and is more likely related to their action at nAChRs containing combinations of α3, α7 or other subunits. Intrathecal nAChR subunitselective conotoxins are therefore promising tools for the effective treatment of neuropathic pain. AbstractThe large diversity of peptides from venomous creatures with high affinity for molecules involved in the development and maintenance of neuropathic pain has led to a surge in venom-derived analgesic research. Some members of the α-conotoxin family from Conus snails which specifically target subtypes of nicotinic acetylcholine receptors (nAChR) have been shown to be effective at reducing mechanical allodynia in neuropathic pain models. We sought to determine if three such peptides, Vc1.1, AuIB and MII were effective following intrathecal administration in a rat neuropathic pain model because they exhibit different affinities for the major putative pain relieving targets of α-conotoxins. Intrathecal administration of α-conotoxins, Vc1.1, AuIB and MII into neuropathic rats reduced mechanical allodynia for up to 6 hours without significant side effects. In vitro patch-clamp electrophysiology of primary afferent synaptic transmission revealed the mode of action of these toxins was not via a GABA B -dependant mechanism, and is more likely related to their action at nAChRs containing combinations of α3, α7 or other subunits. Intrathecal nAChR subunitselective conotoxins are therefore promising tools for the effective treatment of neuropathic pain.3