Adenylyl cyclase types 1 (AC1) and 8 (AC8), the two major calmodulin-stimulated adenylyl cyclases in the brain, couple NMDA receptor activation to cAMP signaling pathways. Cyclic AMP signaling pathways are important for many brain functions, such as learning and memory, drug addiction, and development. Here we show that wild-type, AC1, AC8, or AC1&8 double knockout (DKO) mice were indistinguishable in tests of acute pain, whereas behavioral responses to peripheral injection of two inflammatory stimuli, formalin and complete Freund's adjuvant, were reduced or abolished in AC1&8 DKO mice. AC1 and AC8 are highly expressed in the anterior cingulate cortex (ACC), and contribute to inflammation-induced activation of CREB. Intra-ACC administration of forskolin rescued behavioral allodynia defective in the AC1&8 DKO mice. Our studies suggest that AC1 and AC8 in the ACC selectively contribute to behavioral allodynia.
N-methyl-D-aspartate (NMDA) receptors contribute to many brain functions. We studied the effect of forebrain-targeted overexpression of the NMDA receptor subunit NR2B on the response of mice to tissue injury and inflammation. Transgenic mice exhibited prominent NR2B expression and enhanced NMDA receptor-mediated synaptic responses in two pain-related forebrain areas, the anterior cingulate cortex and insular cortex, but not in the spinal cord. Although transgenic and wild type mice were indistinguishable in tests of acute pain, transgenic mice exhibited enhanced responsiveness to peripheral injection of two inflammatory stimuli, formalin and complete Freund's adjuvant. Genetic modification of forebrain NMDA receptors can therefore influence pain perception, which suggests that forebrain-selective NMDA receptor antagonists, including NR2B-selective agents, may be useful analgesics for persistent pain.
Glutamate, the major excitatory neurotransmitter in the central nervous system, activates three different receptors that directly gate ion channels, namely receptors for AMPA (alpha-amino-3-hydroxy-5-methyl isoxozole propionic acid), NMDA (N-methyl-D-aspartate), and kainate, a structural analogue of glutamate. The contribution of AMPA and NMDA receptors to synaptic transmission and plasticity is well established. Recent work on the physiological function of kainate receptors has focused on the hippocampus, where repetitive activation of the mossy-fibre pathway generates a slow, kainate-receptor-mediated excitatory postsynaptic current (EPSC). Here we show that high-intensity single-shock stimulation (of duration 200 microseconds) of primary afferent sensory fibres produces a fast, kainate-receptor-mediated EPSC in the superficial dorsal horn of the spinal cord. Activation of low-threshold afferent fibres generates typical AMPA-receptor-mediated EPSCs only, indicating that kainate receptors may be restricted to synapses formed by high-threshold nociceptive (pain-sensing) and thermoreceptive primary afferent fibres. Consistent with this possibility, kainate-receptor-mediated EPSCs are blocked by the analgesic mu-opiate-receptor agonist Damgo and spinal blockade of both kainate and AMPA receptors produces antinociception. Thus, spinal kainate receptors contribute to transmission of somatosensory inputs from the periphery to the brain.
It is well documented that the descending endogenous analgesia system, including the periaqueductal gray (PAG) and the rostral ventral medulla (RVM), play an important role in modulation of nociceptive transmission and morphine- and cannabinoid-produced analgesia. Neurons in the PAG receive inputs from different nuclei of higher structures, including the anterior cingulate cortex (ACC). However, it is unclear if stimulation of neurons in the ACC modulates spinal nociceptive transmission. The present study has examined the effects of electrical stimulation and chemical activation of metabotropic glutamate receptors (mGluRs) in the ACC on a spinal nociceptive tail-flick (TF) reflex induced by noxious heating. Activation of the ACC at high intensities (up to 500 microA) of electrical stimulation did not produce any antinociceptive effect. Instead, at most sites within the ACC (n = 36 of 41 sites), electrical stimulation produced significant facilitation of the TF reflex (i.e. decreases in TF latency). Chemical activation of mGluRs within the ACC also produced a facilitatory effect. Descending facilitation from the ACC apparently relays at the RVM. Electrical stimulation in the RVM produces a biphasic modulatory effect, showing facilitation at low intensities and inhibition at higher intensities. The present study provides evidence that activation of mGluRs within the ACC can facilitate spinal nociception.
Using human autoimmune sera as molecular probes, we previously described the association of phosphorylated serine/arginine splicing factors (SR splicing factors) with the U1-small nuclear ribonucleoprotein (U1-snRNP) and U3-small nucleolar RNP (snoRNP) in apoptotic cells. SR proteins are highly conserved autoantigens whose activity is tightly regulated by reversible phosphorylation of serine residues by at least eight different SR protein kinase kinases (SRPKs), including SRPK1, SRPK2, and the scleroderma autoantigen topoisomerase I. In this report, we demonstrate that only one of the known SRPKs, SRPK1, is associated with the U1-snRNP autoantigen complex in healthy and apoptotic cells. SRPK1 is activated early during apoptosis, followed by caspase-mediated proteolytic inactivation at later time points. SRPKs are cleaved in vivo after multiple apoptotic stimuli, and cleavage can be inhibited by overexpression of bcl-2 and bcl-xL, and by exposure to soluble peptide caspase inhibitors. Incubation of recombinant caspases with in vitro–translated SRPKs demonstrates that SRPK1 and SRPK2 are in vitro substrates for caspases-8 and -9, respectively. In contrast, topoisomerase I is cleaved by downstream caspases (-3 and -6). Since each of these SRPKs sits at a distinct checkpoint in the caspase cascade, SRPKs may serve an important role in signaling pathways governing apoptosis, alternative mRNA splicing, SR protein trafficking, RNA stability, and possibly the generation of autoantibodies directed against splicing factors.
Proteins cleaved by apoptotic caspases are commonly recognized by autoantibodies found in the serum of patients with rheumatic disease. We report that the 72-kDa signal recognition particle (SRP) protein, a rare target of autoantibodies found in the serum of patients with dermatomyositis and systemic lupus erythematosus, is rapidly cleaved in Jurkat T cells treated with apoptotic (i.e. Fas ligation, treatment with ␥ or ultraviolet radiation, or co-culture with anisomycin or staurosporine) but not proliferative (CD3 cross-linking) stimuli. Cleavage of SRP 72 produces a 66-kDa amino-terminal fragment and a 6-kDa carboxyl-terminal fragment that is selectively phosphorylated on serine residues. Cleavage of SRP 72 is prevented by chemical and peptide caspase inhibitors, and by overexpression of bcl-2, an inhibitor of apoptotic cell death. Analysis of the carboxyl terminus of SRP 72 has identified a putative cleavage site (SELD/A) for group III caspases, and carboxyl-terminal serine residues that are highly conserved in phylogeny. Both serine phosphorylation and caspase cleavage of SRP 72 are observed in cells derived from human, dog, rat, and mouse. Canine SRP 72 is cleaved in vitro by recombinant caspase 3 but retains the ability to mediate transport of a signal peptide-containing protein into the endoplasmic reticulum lumen. The 72-kDa component of the SRP joins a growing list of autoantigens that undergo post-translational modifications during programmed cell death.Proteins modified by the proteases and kinases that are activated during apoptosis are often involved in both the execution phase of cell death and in the development of autoantibodies in patients with systemic lupus erythematosus and mixed connective tissue disease (reviewed in Ref. 1). For example, at least 17 proteins that are known to be cleaved by caspases during apoptosis are autoantigens, including the 70-kDa component of the U1-small nuclear ribonuclear protein complex (U1-70 kDa) (2), poly(A) ribose polymerase (3), DNAdependent protein kinase (DNA-PK) (4), hnRNP C1 and C2 (5), lamins A, B, and C (6), the nuclear mitotic apparatus protein (NuMA) (7, 8), topoisomerases 1 and 2 (8), the nucleolar protein UBF/NOR-90 (8), and ␣-fodrin (9, 10) (reviewed in Ref. 1). In addition, phosphorylated serine/arginine splicing factors have recently been shown to specifically associate with the U1-small nuclear RNP autoantigen complex during apoptosis (11, 12). These observations have led to the hypothesis that proteins modified during apoptosis can be presented to the immune system in a way that bypasses tolerance to self proteins. Although the molecular mechanisms by which this occurs are not known, the data suggests that patient-derived autoantisera may be useful in the identification of proteins that contribute to the execution phase of apoptosis.While screening a panel of human autoantisera for their ability to precipitate new phosphoproteins from apoptotic Jurkat cell lysates, we serendipitously identified several sera that precipitated phosphoproteins fr...
Dermatologic surgeons should be aware of patients with devices implanted in the CNS with electrical activity and proceed with caution when using electrosurgery. Different approaches can be utilized to help reduce adverse effects.
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