Unidirectional cross-activation of GRPR by MOR1D uncouples itch and analgesia induced by opioids.

Spinal opioid-induced itch, a prevalent side effect of pain management, has been proposed to result from pain inhibition. We now report that the µ-opioid receptor (MOR) isoform MOR1D is essential for morphine-induced scratching (MIS), whereas the isoform MOR1 is required only for morphine-induced analgesia (MIA). MOR1D heterodimerizes with gastrin-releasing peptide receptor (GRPR) in the spinal cord, relaying itch information. We show that morphine triggers internalization of both GRPR and MOR1D, whereas GRP specifically triggers GRPR internalization and morphine-independent scratching. Providing potential insight into opioid-induced itch prevention, we demonstrate that molecular and pharmacologic inhibition of PLCß3 and IP3R3, downstream effectors of GRPR, specifically block MIS but not MIA. In addition, blocking MOR1D-GRPR association attenuates MIS but not MIA. Together, these data suggest that opioid-induced itch is an active process concomitant with but independent of opioid analgesia, occurring via the unidirectional cross-activation of GRPR signaling by MOR1D heterodimerization.

Cross-talk between Human Spinal Cord µ-opioid Receptor 1Y Isoform and Gastrin-releasing Peptide Receptor Mediates Opioid-induced Scratching Behavior.

BACKGROUND: Although spinal opioids are safe and effective, pruritus is common and distressing. The authors previously demonstrated in mouse spinal cord that interactions between µ-opioid receptor isoform 1D and gastrin releasing peptide receptor mediate morphine-induced scratch. The C-terminal of 1D inhibits morphine-induced scratch without affecting analgesia. The authors hypothesize that human spinal cord also contains itch-specific µ-opioid receptor isoforms which interact with gastrin releasing peptide receptor. METHODS: Reverse transcription polymerase chain reaction was performed on human spinal cord complimentary DNA from two human cadavers. Calcium responses to morphine (1 µM) were examined using calcium imaging microscopy on human cells (HEK293) coexpressing gastrin releasing peptide receptor and different human µ-opioid receptor isoforms. The authors assessed morphine-induced scratching behavior and thermal analgesia in mice following intrathecal injection of morphine (0.3 nmol) and a transactivator of transcription peptide designed from C-terminal sequences of 1Y isoform (0, 0.1, and 0.4 nmol). RESULTS: The authors demonstrated 1Y expression in the spinal cord dorsal horn. Morphine administration evoked a calcium response (mean ± SD) (57 ± 13 nM) in cells coexpressing both gastrin releasing peptide receptor and the 1Y isomer. This was blocked by 10 µM naltrexone (0.7 ± 0.4 nM; P < 0.0001), 1 µM gastrin-releasing peptide receptor antagonist (3 ± 2 nM; P < 0.0001), or 200 µM 1Y-peptide (2 + 2 nM; P < 0.0001). In mice, 0.4 nmol 1Y-peptide significantly attenuated morphine-induced scratching behaviors (scratching bouts, vehicle vs. 1Y-peptide) (92 ± 31 vs. 38 ± 29; P = 0.011; n = 6 to 7 mice per group), without affecting morphine antinociception in warm water tail immersion test (% of maximum possible effect) (70 ± 21 vs. 67 ± 22; P = 0.80; n = 6 mice per group). CONCLUSIONS: Human µ-opioid receptor 1Y isomer is a C-terminal splicing variant of Oprm1 gene identified in human spinal cord. Cross-talk between 1Y and gastrin releasing peptide receptor is required for mediating opioid-induced pruritus. Disrupting the cross talk may have implications for therapeutic uncoupling of desired analgesic effects from side effects of opioids.

Critical evaluation of the expression of gastrin-releasing peptide in dorsal root ganglia and spinal cord.

There are substantial disagreements about the expression of gastrin-releasing peptide (GRP) in sensory neurons and whether GRP antibody cross-reacts with substance P (SP). These concerns necessitate a critical revaluation of GRP expression using additional approaches. Here, we show that a widely used GRP antibody specifically recognizes GRP but not SP. In the spinal cord of mice lacking SP (Tac1KO), the expression of not only GRP but also other peptides, notably neuropeptide Y (NPY), is significantly diminished. We detectedGrpmRNA in dorsal root ganglias using reverse transcription polymerase chain reaction, in situ hybridization and RNA-seq. We demonstrated thatGrpmRNA and protein are upregulated in dorsal root ganglias, but not in the spinal cord, of mice with chronic itch. Few GRP(+)immunostaining signals were detected in spinal sections following dorsal rhizotomy and GRP(+)cell bodies were not detected in dissociated dorsal horn neurons. Ultrastructural analysis further shows that substantially more GRPergic fibers form synaptic contacts with gastrin releasing peptide receptor-positive (GRPR(+)) neurons than SPergic fibers. Our comprehensive study demonstrates that a majority of GRPergic fibers are of primary afferent origin. A number of factors such as low copy number ofGrptranscripts, small percentage of cells expressingGrp, and the use of an eGFP GENSAT transgenic as a surrogate for GRP protein have contributed to the controversy. Optimization of experimental procedures facilitates the specific detection of GRP expression in dorsal root ganglia neurons.

[The Gemological Characteristics of One Kind Turquoise Imitation].

It has been a long time that the imitations of turquoise appear in gem market. Pressed dyed carbonate in the early stage and dyed variscite, chalcedony as well as magnesite appeared in succession. These kinds of materials do not have the color and characteristics of natural turquoise. Their physical and optical properties are quite different from natural turquoise. One kind of turquoise imitation newly appears in market is selected to be studied in this paper. The conventional gemological method, infrared absorption spectroscopy and X-ray diffraction were employed to study its mineral compositions, gemological properties and structural characteristics. The results show that: the brecciated structure can be observed and the distribution of the iron wire is very simple on the surface of the sample. Deep blue granules are visible on the surface of blue samples and a few black spots can be observed on the surface of white ones, which are typical indication of pressing process. The blue imitations of turquoise has been stained and pressed. The index of this kind of turquoise imitation range from 1.54 to 1.58, which is lower than that of natural turquoise and it show bluish white fluorescence, which can be used as important evidence to distinguish it with natural turquoise. The data of X-ray diffraction shows the sample mainly consists of enstatite and quartz. The results of infrared absorption spectroscopy show that the absorption spectra of this kind of turquoise imitation is in accordance with the typical absorption peaks of enstatite: the absorption peaks which locates near 1 088 and 799 cm-1 are associated with Si­O, Si­O­Si stretching vibration in quartz; the absorption peaks near 2 947 and 2 882 cm-1 is related with stretching vibration of CH2 of exotic organic resin; the absorption peaks near 1 736 and 1 510 cm-1 are resulted from the bending and stretching vibration of CO and CH2.

Cross-inhibition of NMBR and GRPR signaling maintains normal histaminergic itch transmission.

We previously showed that gastrin-releasing peptide receptor (GRPR) in the spinal cord is important for mediating nonhistaminergic itch. Neuromedin B receptor (NMBR), the second member of the mammalian bombesin receptor family, is expressed in a largely nonoverlapping pattern with GRPR in the superficial spinal cord, and its role in itch transmission remains unclear. Here, we report that Nmbr knock-out (KO) mice exhibited normal scratching behavior in response to intradermal injection of pruritogens. However, mice lacking both Nmbr and Grpr (DKO mice) showed significant deficits in histaminergic itch. In contrast, the chloroquine (CQ)-evoked scratching behavior of DKO mice is not further reduced compared with Grpr KO mice. These results suggest that NMBR and GRPR could compensate for the loss of each other to maintain normal histamine-evoked itch, whereas GRPR is exclusively required for CQ-evoked scratching behavior. Interestingly, GRPR activity is enhanced in Nmbr KO mice despite the lack of upregulation of Grpr expression; so is NMBR in Grpr KO mice. We found that NMB acts exclusively through NMBR for itch transmission, whereas GRP can signal through both receptors, albeit to NMBR to a much lesser extent. Although NMBR and NMBR(+) neurons are dispensable for histaminergic itch, GRPR(+) neurons are likely to act downstream of NMBR(+) neurons to integrate NMB-NMBR-encoded histaminergic itch information in normal physiological conditions. Together, we define the respective function of NMBR and GRPR in itch transmission, and reveal an unexpected relationship not only between the two receptors but also between the two populations of interneurons in itch signaling.

[Study on Vibrational Spectra Characteristics of Gem-Quality Natrolite].

Recently, there is a batch of colorless faceted gem-quality natrolite appear in the international jewelry market. In order to provide some information that can help us to distinguish them from the imitations. The infrared spectrometer and Raman spectrometer were employed to study the characteristics of the vibrational spectrum of three natrolite samples in this article. The typical infrared spectra shows that: the absorption region 4000~1200 cm(-1) is induced by stretching vibration of the hydroxyl group, the strong absorption peaks range from 1200~600 cm(-1) are relative with the anti-symmetry and symmetry stretching vibration of tetrahedral T-O bonds (T=Si or Al). The Raman spectra scattering peaks are located in the range of 300~600 and 700~1200 cm(-1). The low intensity Raman scattering spectrum in the range of 300~360 cm(-1) corresponds to the vibration of the water molecules in the crystal. The medium intensity Raman scattering spectrum is assigned to the deformation of SiO4 tetrahedra. The Raman spectra scattering peak at 726 cm(-1) is assigned to the stretching vibration of Al-O; The Si-O stretching vibration displays the Raman spectra scattering peaks at 974, 1038 and 1084 cm(-1).

B-type natriuretic peptide is neither itch-specific nor functions upstream of the GRP-GRPR signaling pathway.

BACKGROUND: A recent study by Mishra and Hoon identified B-type natriuretic peptide (BNP) as an important peptide for itch transmission and proposed that BNP activates spinal natriuretic peptide receptor-A (NPRA) expressing neurons, which release gastrin releasing peptide (GRP) to activate GRP receptor (GRPR) expressing neurons to relay itch information from the periphery to the brain (Science 340:968-971, 2013). A central premise for the validity of this novel pathway is the absence of GRP in the dorsal root ganglion (DRG) neurons. To this end, they showed that Grp mRNA in DRG neurons is either absent or barely detectable and claimed that BNP but not GRP is a major neurotransmitter for itch in pruriceptors. They showed that NPRA immunostaining is perfectly co-localized with Grp-eGFP in the spinal cord, and a few acute pain behaviors in Nppb-/- mice were tested. They claimed that BNP is an itch-selective peptide that acts as the first station of a dedicated neuronal pathway comprising a GRP-GRPR cascade for itch. However, our studies, along with the others, do not support their claims. FINDINGS: We were unable to reproduce the immunostaining of BNP and NPRA as shown by Mishra and Hoon. By contrast, we were able to detect Grp mRNA in DRGs using in situ hybridization and real time RT-PCR. We show that the expression pattern of Grp mRNA is comparable to that of GRP protein in DRGs. Pharmacological and genetic blockade of GRP-GRPR signaling does not significantly affect intrathecal BNP-induced scratching behavior. We show that BNP inhibits inflammatory pain and morphine analgesia. CONCLUSIONS: Accumulating evidence demonstrates that GRP is a key neurotransmitter in pruriceptors for mediating histamine-independent itch. BNP-NPRA signaling is involved in both itch and pain and does not function upstream of the GRP-GRPR dedicated neuronal pathway. The site of BNP action in itch and pain and its relationship with GRP remain to be clarified.

CaMKIIalpha interacts with M4 muscarinic receptors to control receptor and psychomotor function.

Muscarinic acetylcholine receptors (mAChRs) are widely expressed in the mammalian brain and are essential for neuronal functions. These receptors are believed to be actively regulated by intracellular signals, although the underlying mechanisms are largely unknown. In this study, we show that Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) binds directly and selectively to one of five mAChR subtypes, M4 receptors (M4Rs), at their C-terminal regions of second intracellular loops. This binding relies on Ca(2+) activation of the kinase and leads to the phosphorylation of M4Rs at a specific threonine site (Thr145). Complementary in vivo studies in rat striatal neurons enriched with M4Rs confirm that rising Ca(2+) recruits CaMKIIalpha to M4Rs to potentiate receptor signalling, which controls behavioural sensitivity to dopamine stimulation in an activity-dependent manner. Our data identify a new model of protein-protein interactions. In a Ca(2+)-sensitive manner, CaMKIIalpha regulates M4R efficacy and controls the acetylcholine-dopamine balance in the basal ganglia and also the dynamics of movement.

BNP facilitates NMB-encoded histaminergic itch via NPRC-NMBR crosstalk.

Histamine-dependent and -independent itch is conveyed by parallel peripheral neural pathways that express gastrin-releasing peptide (GRP) and neuromedin B (NMB), respectively, to the spinal cord of mice. B-type natriuretic peptide (BNP) has been proposed to transmit both types of itch via its receptor NPRA encoded by Npr1. However, BNP also binds to its cognate receptor, NPRC encoded by Npr3 with equal potency. Moreover, natriuretic peptides (NP) signal through the Gi-couped inhibitory cGMP pathway that is supposed to inhibit neuronal activity, raising the question of how BNP may transmit itch information. Here, we report that Npr3 expression in laminae I-II of the dorsal horn partially overlaps with NMB receptor (NMBR) that transmits histaminergic itch via Gq-couped PLCß-Ca2+ signaling pathway. Functional studies indicate that NPRC is required for itch evoked by histamine but not chloroquine (CQ), a nonhistaminergic pruritogen. Importantly, BNP significantly facilitates scratching behaviors mediated by NMB, but not GRP. Consistently, BNP evoked Ca2+ responses in NMBR/NPRC HEK 293 cells and NMBR/NPRC dorsal horn neurons. These results reveal a previously unknown mechanism by which BNP facilitates NMB-encoded itch through a novel NPRC-NMBR cross-signaling in mice. Our studies uncover distinct modes of action for neuropeptides in transmission and modulation of itch in mice.

An itch is a common sensation that makes us want to scratch. Most short-term itches are caused by histamine, a chemical that is released by immune cells following an infection or in response to an allergic reaction. Chronic itching, on the other hand, is not usually triggered by histamine, and is typically the result of neurological or skin disorders, such as atopic dermatitis. The sensation of itching is generated by signals that travel from the skin to nerve cells in the spinal cord. Studies in mice have shown that the neuropeptides responsible for delivering these signals differ depending on whether or not the itch involves histamine: GRPs (short for gastrin-releasing proteins) convey histamine-independent itches, while NMBs (short for neuromedin B) convey histamine-dependent itches. It has been proposed that another neuropeptide called BNP (short for B-type natriuretic peptide) is able to transmit both types of itch signals to the spinal cord. But it remains unclear how this signaling molecule is able to do this. To investigate, Meng, Liu, Liu, Liu et al. carried out a combination of behavioral, molecular and pharmacological experiments in mice and nerve cells cultured in a laboratory. The experiments showed that BNP alone cannot transmit the sensation of itching, but it can boost itching signals that are triggered by histamine. It is widely believed that BNP activates a receptor protein called NPRA. However, Meng et al. found that the BNP actually binds to another protein which alters the function of the receptor activated by NMBs. These findings suggest that BNP modulates rather than initiates histamine-dependent itching by enhancing the interaction between NMBs and their receptor. Understanding how itch signals travel from the skin to neurons in the spinal cord is crucial for designing new treatments for chronic itching. The work by Meng et al. suggests that treatments targeting NPRA, which was thought to be a key itch receptor, may not be effective against chronic itching, and that other drug targets need to be explored.

Modulation of D2R-NR2B interactions in response to cocaine.

Dopamine-glutamate interactions in the neostriatum determine psychostimulant action, but the underlying molecular mechanisms remain elusive. Here we found that dopamine stimulation by cocaine enhances a heteroreceptor complex formation between dopamine D2 receptors (D2R) and NMDA receptor NR2B subunits in the neostriatum in vivo. The D2R-NR2B interaction is direct and occurs in the confined postsynaptic density microdomain of excitatory synapses. The enhanced D2R-NR2B interaction disrupts the association of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) with NR2B, reduces NR2B phosphorylation at a CaMKII-sensitive site (Ser1303), and inhibits NMDA receptor-mediated currents in medium-sized striatal neurons. Furthermore, the regulated D2R-NR2B interaction is critical for constructing behavioral responsiveness to cocaine. Our findings here uncover a direct and dynamic D2R-NR2B interaction in striatal neurons in vivo. This type of dopamine-glutamate integration at the receptor level may be responsible for synergistically inhibiting the D2R-mediated circuits in the basal ganglia and fulfilling the stimulative effect of psychostimulants.

Molecular logic circuit based on a multi-state mononuclear platinum(ii) terpyridyl complex.

A new type of multi-state platinum(ii) terpyridyl acetylide complex: platinum(ii) 4'-(4-dimethylaminophenyl)-2,2' : 6',2''-terpyridyl ferrocenyl acetylide (1), together with its reference complexes: platinum(ii) 4'-(4-methylphenyl)-2,2' : 6',2''-terpyridyl ferrocenyl acetylide (2), platinum(ii) 4'-(4-dimethylaminophenyl)-2,2' : 6',2''-terpyridyl phenyl acetylide (3) and platinum(ii) 4'-(4-methylphenyl)-2,2' : 6',2''-terpyridyl phenyl acetylide (4), are designed and synthesized. UV-vis-NIR absorption and electrochemical studies demonstrate that complex 1 possesses three ordered intraligand charge transfer (ILCT), ligand-to-ligand charge transfer (LLCT) and metal-to-ligand charge transfer (MLCT) states, and the successive modulation of the intramolecular ILCT, LLCT and MLCT states in a single mononuclear platinum(ii) complex 1 is well evidenced by their reference complexes 2-4. More interestingly, a near-infrared absorption band ranging from 720-1000 nm was clearly observed for complexes 1 and 2 upon oxidation of the σ-bonded ferrocene-ethynyl group by Fe(ClO(4))(3), which was tentatively assigned to platinum(ii)-disturbed ligand-to-metal charge transfer (LM'CT) of the ferrocenium group. These promising features allow us to integrate the multiple states to reproduce basic logic operations at the molecular level. A four-state (LLCT, ILCT, MLCT and LM'CT) molecular switch of complex 1 that responds to the stimulation of H(+), Fe(ClO(4))(3) and Zn producing four outputs has been encoded in binary digits. The logic function executed by complex 1 is equivalent to that of a combinational logic circuit integrating seven or eight logic functions as AND, OR, NOT. A three-input-four-output molecular logic circuit has been established.

Exploration of sensory and spinal neurons expressing gastrin-releasing peptide in itch and pain related behaviors.

Gastrin-releasing peptide (GRP) functions as a neurotransmitter for non-histaminergic itch, but its site of action (sensory neurons vs spinal cord) remains controversial. To determine the role of GRP in sensory neurons, we generated a floxed Grp mouse line. We found that conditional knockout of Grp in sensory neurons results in attenuated non-histaminergic itch, without impairing histamine-induced itch. Using a Grp-Cre knock-in mouse line, we show that the upper epidermis of the skin is exclusively innervated by GRP fibers, whose activation via optogeneics and chemogenetics in the skin evokes itch- but not pain-related scratching or wiping behaviors. In contrast, intersectional genetic ablation of spinal Grp neurons does not affect itch nor pain transmission, demonstrating that spinal Grp neurons are dispensable for itch transmission. These data indicate that GRP is a neuropeptide in sensory neurons for non-histaminergic itch, and GRP sensory neurons are dedicated to itch transmission.

A spinal neural circuitry for converting touch to itch sensation.

Touch and itch sensations are crucial for evoking defensive and emotional responses, and light tactile touch may induce unpleasant itch sensations (mechanical itch or alloknesis). The neural substrate for touch-to-itch conversion in the spinal cord remains elusive. We report that spinal interneurons expressing Tachykinin 2-Cre (Tac2Cre) receive direct Aß low threshold mechanoreceptor (LTMR) input and form monosynaptic connections with GRPR neurons. Ablation or inhibition markedly reduces mechanical but not acute chemical itch nor noxious touch information. Chemogenetic inhibition of Tac2Cre neurons also displays pronounced deficit in chronic dry skin itch, a type of chemical itch in mice. Consistently, ablation of gastrin-releasing peptide receptor (GRPR) neurons, which are essential for transmitting chemical itch, also abolishes mechanical itch. Together, these results suggest that innocuous touch and chemical itch information converge on GRPR neurons and thus map an exquisite spinal circuitry hard-wired for converting innocuous touch to irritating itch.

PAR2 Mediates Itch via TRPV3 Signaling in Keratinocytes.

Animal studies have suggested that transient receptor potential ion channels and G-protein coupled receptors play important roles in itch transmission. TRPV3 gain-of-function mutations have been identified in patients with Olmsted syndrome, which is associated with severe pruritus. However, the mechanisms causing itch remain poorly understood. Here, we show that keratinocytes lacking TRPV3 impair the function of protease-activated receptor 2 (PAR2), resulting in reduced neuronal activation and scratching behavior in response to PAR2 agonists. Moreover, we show that TRPV3 and PAR2 were upregulated in skin biopsies from patients and mice with atopic dermatitis, whereas their inhibition attenuated scratching and inflammatory responses in mouse atopic dermatitis models. These results reveal a previously unrecognized link between TRPV3 and PAR2 in keratinocytes to convey itch information and suggest that a blockade of PAR2 or TRPV3 individually or both may serve as a potential approach for antipruritic therapy in atopic dermatitis.

Three and Six Months of Ketogenic Diet for Intractable Childhood Epilepsy: A Systematic Review and Meta-Analysis.

Objective: The ketogenic diet (KD) has been an effective antiepileptic treatment for intractable childhood epilepsy. The appropriate timing to evaluate the effect of KD is 3 months which is still not defined statistically. Therefore, we aim to realistically assess whether spasm remission during the period of 3 months KD can be a prediction index for the therapeutic effect of 6 months treatment. Methods: To investigate the duration and effect of the KD therapy for intractable childhood epilepsy, we searched the relevant articles up to May 20, 2018 from PubMed, Cochrane, Embase, Ovid, Web of Science, Google Scholar, and Conference literature. The inclusion criteria were: (i) confirmed cases of intractable childhood epilepsy, (ii) specific 3 and 6 months follow-up time, (iii) classified spasm remission evaluation. The exclusion criteria were: (i) including other therapy, (ii) unspecific follow-up time, (iii) no specific index for seizure reduction. The data extracted by two researchers independently included proportion of KD duration, seizure remission, year of publication, author, study design, and diet varieties. Results: The search strategy included a total of 542 citations, 18 articles were met the criteria with a total of 1,062 patients included in the final analysis. Compared with 3 and 6 months KD treatment, the rate difference of 50% seizure reduction was -0.01(95% CI: -0.09 to 0.06). And 90% seizure reduction was -0.036(95% CI: -0.090 to 0.017) and seizure free was -0.031(95% CI: -0.081 to 0.020). Conclusion: This meta-analysis provides statistical support that a period of 3 months KD can be a prediction index of 6 months duration in term of spasm remission. The 3 months KD can be implemented to evaluate seizure remission timely and provide personalized early support.

Phosphorylation of group I metabotropic glutamate receptors (mGluR1/5) in vitro and in vivo.

Group I metabotropic glutamate receptors (mGluR1 and mGluR5 subtypes) are densely expressed in mammalian brain. They are actively involved in the regulation of normal cellular activity and synaptic plasticity, and are frequently linked to the pathogenesis of various mental illnesses. Like ionotropic glutamate receptors, group I mGluRs are subject to the regulation by protein phosphorylation. Accumulative data demonstrate sufficient phosphorylation of the intracellular mGluR1/5 domains at specific serine/threonine sites by protein kinase C in heterologous cells or neurons, which serves as an important mechanism for regulating the receptor signaling and desensitization. Emerging evidence also shows the significant involvements of G protein-coupled receptor kinases, Ca2+/calmodulin-dependent protein kinase II, tyrosine kinases, and protein phosphatases in controlling the phosphorylation status of group I mGluRs. This review analyzes the recent data concerning group I mGluR phosphorylation and the phosphorylation-dependent regulation of group I mGluR function. Future research directions in this area with newly available high throughput and proteomic approaches are also discussed in the end.

Group I metabotropic glutamate receptor-mediated gene expression in striatal neurons.

Group I mGluRs (mGluR1/5) are G-protein-coupled receptors and are abundantly expressed in most of medium spiny projection neurons in the striatum. Recent evidence demonstrates that group I mGluRs are among essential regulators for constitutive and inducible gene expression in host neurons. Upon activation, mGluR1/5 signals activate extracellular signal-regulated kinases (ERKs) which in turn phosphorylate transcription factors such as cAMP response element-binding protein (CREB) and Elk-1, and thereby facilitate immediate early gene and opioid peptide gene expression. The conventional mGluR1/5 signaling cascade (phosphoinositide hydrolysis and intracellular Ca(2+) release) participates in linking mGluR1/5 to ERK. Additionally, the prominent mGluR1/5 adaptor protein Homer contributes to assemble an efficient signaling apparatus connecting mGluR1/5 to gene expression. The mGluR1/5 linkage to transcription also functions in dopamine-stimulated gene expression. Together, the mGluR1/5-mediated gene expression constitutes a transcription-dependent mechanism underlying molecular adaptations and plasticity related to the pathogenesis of various mental illnesses.

Therapeutic strategies for Parkinson's disease: the ancient meets the future--traditional Chinese herbal medicine, electroacupuncture, gene therapy and stem cells.

In China, it has been estimated that there are more than 2.0 million people suffering from Parkinson's disease, which is currently becoming one of the most common chronic neurodegenerative disorders during recent years. For many years, scientists have struggled to find new therapeutic approaches for this disease. Since 1994, our research group led by Drs. Ji-Sheng Han and Xiao-Min Wang of Neuroscience Research Institute, Peking University has developed several prospective treatment strategies for the disease. These studies cover the traditional Chinese medicine-herbal formula or acupuncture, and modern technologies such as gene therapy or stem cell replacement therapy, and have achieved some original results. It hopes that these data may be beneficial for the research development and for the future clinical utility for treatment of Parkinson's disease.

The effect of metformin treatment on endoplasmic reticulum (ER) stress induced by status epilepticus (SE) via the PERK-eIF2α-CHOP pathway.

Status epilepticus (SE) is defined as continuous seizure activity lasting more than 5 minutes. It results in neuronal cell death, mediated by endoplasmic reticulum (ER) stress response. Previously, metformin demonstrated neuroprotective effects in primary cortical neurons. In this study, we analyzed the effect of metformin on ER stress via the pro-apoptotic protein kinase RNA-like endoplasmic reticulum kinase (PERK)-eukaryotic initiation factor 2α (eIF2α)-C/EBP homologous protein (CHOP) pathway. SE was induced in rats by pentylenetetrazole. Following SE, the rats were treated with salubrinal, GSK2656157, or metformin. In a control group (normal saline) SE was not induced. CHOP, eIF2α, and PERK expression was determined by Western blot; apoptosis was analyzed by TUNEL assay. CHOP expression was significantly increased at 6 and 24 hours following SE. At both time points, eIF2α and PERK levels were also increased. At 6 hours, CHOP expression was significantly reduced in salubrinal, GSK2656157 and metformin groups versus SE group. eIF2α and PERK levels were decreased in metformin compared to SE group. eIF2α expression was markedly decreased in salubrinal versus SE group, while PERK expression was markedly reduced in GSK2656157 versus SE group. At 6 and 24 hours, the apoptosis rate was significantly increased in SE versus control group, while it was significantly reduced in salubrinal, GSK2656157, and metformin groups compared to SE group. The apoptosis rate also decreased in salubrinal group at 24 hours, although not to the extent observed in metformin group. Overall, CHOP expression and apoptosis induced by SE in rats were reduced with metformin. Further studies are required to evaluate the clinical relevance of metformin for patients with SE.