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1.  Identification of a Receptor for Neuropeptide VGF and Its Role in Neuropathic Pain* 
The Journal of Biological Chemistry  2013;288(48):34638-34646.
Background: VGF is a neuropeptide involved in chronic pain.
Results: VGF-derived peptide TLQP-21 activates macrophages. We identified gC1qR as a receptor for TLQP-21.
Conclusion: TLQP-21 and gC1qR are involved in chronic pain pathways.
Significance: TLQP-21 and gC1qR may be drug targets for chronic pain treatment.
VGF (nonacronymic) is a neuropeptide precursor that plays multiple roles in regulation of energy balance, reproduction, hippocampal synaptic plasticity, and pain. Data from a number of pain models showed significant up-regulation of VGF in sensory neurons. TLQP-21, one of the VGF-derived neuropeptides, has been shown to induce a hyperalgesic response when injected subcutaneously into the hind paw of mice. However, the precise role of VGF-derived neuropeptides in neuropathic pain and the molecular identity of the receptor for VGF-derived peptides are yet to be investigated. Here we identified gC1qR, the globular heads of the C1q receptor, as the receptor for TLQP-21 using chemical cross-linking combined with mass spectrometry analysis. TLQP-21 caused an increase in intracellular Ca2+ levels in rat macrophages and microglia. Inoculation of TLQP-21-stimulated macrophages into rat hind paw caused mechanical hypersensitivity. The increase in intracellular Ca2+ levels in macrophages was attenuated by either siRNA or neutralizing antibodies against gC1qR. Furthermore, application of the gC1qR-neutralizing antibody to rats with partial sciatic nerve ligation resulted in a delayed onset of nerve injury-associated mechanical hypersensitivity. These results indicate that gC1qR is the receptor for TLQP-21 and plays an important role in chronic pain through activation of macrophages. Because direct association between TLQP-21 and gC1qR is required for activation of macrophages and causes hypersensitivity, disrupting this interaction may be a useful new approach to develop novel analgesics.
doi:10.1074/jbc.M113.510917
PMCID: PMC3843076  PMID: 24106277
Calcium Intracellular Release; Macrophages; Neurons; Neuropeptide; Pain; VGF; gC1qR; Neuropathic Pain; Sensory Neurons
2.  The trafficking of NaV1.8 
Neuroscience Letters  2010;486(2-13):78-83.
Research highlights
▶ The β3 subunit masks the ER retention signal of NaV1.8 and release the channel from the ER. ▶ p11 directly binds to NaV1.8 and help its translocation to the plasma membrane. ▶ PDZD2 is responsible for the functional expression of NaV1.8 on the plasma membrane. ▶ Contactin KO mice exhibit a reduction of NaV1.8 along unmyelinated axons in the sciatic nerve. ▶ PKA activation increases the NaV1.8 density on the membrane through direct phosphorylation.
The α-subunit of tetrodotoxin-resistant voltage-gated sodium channel NaV1.8 is selectively expressed in sensory neurons. It has been reported that NaV1.8 is involved in the transmission of nociceptive information from sensory neurons to the central nervous system in nociceptive [1] and neuropathic [24] pain conditions. Thus NaV1.8 has been a promising target to treat chronic pain. Here we discuss the recent advances in the study of trafficking mechanism of NaV1.8. These pieces of information are particularly important as such trafficking machinery could be new targets for painkillers.
doi:10.1016/j.neulet.2010.08.074
PMCID: PMC2977848  PMID: 20816723
Sodium Channel; Sensory Neuron; Pain; Trafficking
3.  Protein motions during catalysis by dihydrofolate reductases 
Dihydrofolate reductase (DHFR) maintains the intracellular pool of tetrahydrofolate through catalysis of hydrogen transfer from reduced nicotinamide adenine dinucleotide to 7,8-dihydrofolate. We report results for pre-steady-state kinetic studies of the temperature dependence of the rates and the hydrogen/deuterium-kinetic isotope effects for the reactions catalysed by the enzymes from the mesophilic Escherichia coli and the hyperthermophilic Thermatoga maritima. We propose an evolutionary pattern in which catalysis progressed from a relatively rigid active site structure in the ancient thermophilic DHFR to a more flexible and kinetically more efficient structure in E. coli that actively promotes hydrogen transfer at physiological pH by modulating the tunnelling distance. The E. coli enzyme appeared relatively robust, in that kinetically severely compromised mutants still actively propagated the reaction. The reduced hydrogen transfer rates of the extensively studied Gly121Val mutant of DHFR from E. coli were most likely due to sterically unfavourable long-range effects from the introduction of the bulky isopropyl group.
doi:10.1098/rstb.2006.1865
PMCID: PMC1647303  PMID: 16873119
hydrogen transfer; kinetic isotope effects; protein dynamics; catalysis; enzymes

Results 1-3 (3)