Acid-sensing ion channel 3 (ASIC3), a proton-gated ion channel of the degenerins͞epithelial sodium channel (DEG͞ENaC) receptor family is expressed predominantly in sensory neurons including nociceptive neurons responding to protons. To study the role of ASIC3 in pain signaling, we generated ASIC3 knockout mice. Mutant animals were healthy and responded normally to most sensory stimuli. However, in behavioral assays for pain responses, ASIC3 null mutant mice displayed a reduced latency to the onset of pain responses, or more pain-related behaviors, when stimuli of moderate to high intensity were used. This unexpected effect seemed independent of the modality of the stimulus and was observed in the acetic acid-induced writhing test (0.6 vs. 0.1-0.5%), in the hot-plate test (52.5 and 55 vs. 50°C), and in tests for mechanically induced pain (tail-pinch vs. von Frey filaments). We postulate that ASIC3 is involved in modulating moderate-to high-intensity pain sensation. C ation channels of the degenerin͞epithelial sodium channel family (DEG͞ENaC) have been proposed as transducers of somatosensory stimuli in several species (1). The structural hallmarks of these proteins are two hydrophobic transmembrane domains, with short N and C termini and a large extracellular loop. In vertebrates, the DEG͞ENaC family includes several related subunits of Na ϩ -selective (P NA ͞P K , 8-40) acid-sensing ion channels (ASIC1a, ASIC1b, ASIC2a, ASC2b, ASIC3, and ASIC4; previously named ASIC-␣͞BNC2, ASIC-, MDEG1͞ BNC1, MDEG2, DRASIC, and SPASIC, respectively) (2-4). ASIC proteins associate as homo-or heteromultimers to form functional receptors. Because these receptors are gated by protons, it has been suggested that they might be involved in the perception of pain during tissue acidosis (5). However, there is evidence also that they are involved in mechanosensation; many DEG͞ENaC proteins are localized to mechanosensitive cells in Caenorhabditis elegans, Drosophila melanogaster, rat, and mouse (1, 6, 7). In C. elegans, mutations in DEG͞ENaC proteins such as MEC-4 and MEC-10 lead to impaired touch responses (8,9), and the targeted deletion of ASIC2 in mice resulted in a reduced sensitivity of low-threshold mechanoreceptors (7).One member of the ASIC family, ASIC3, seems to be a particularly good candidate for the transduction of proton and mechanical stimuli, because ASIC3 is expressed predominantly in dorsal root ganglia neurons (10) including large-diameter mechanoreceptors and unmyelinated small-diameter peptidergic nociceptors (3, 6, 11). In addition, ASIC3 protein was found to be present in sensory nerve terminals in Meissner corpuscles lanceolate fibers, which correspond to rapidly adapting lowthreshold mechanoreceptors, as well as in free nerve endings, which may correspond to nociceptors (6).Previous studies have shown that ASIC3 can be activated by protons and generate biphasic inward currents when it was expressed in heterologous cells (12). A transient inward current can be induced when extracellular pH falls to 7.0, which is...
To investigate the events leading to initiation of DNA replication in mammalian chromosomes, the time when hamster origin recognition complexes (ORCs) became functional was related to the time when Orc1, Orc2 and Mcm3 proteins became stably bound to hamster chromatin. Functional ORCs, defined as those able to initiate DNA replication, were absent during mitosis and early G1 phase, and reappeared as cells progressed through G1 phase. Immunoblotting analysis revealed that hamster Orc1 and Orc2 proteins were present in nuclei at equivalent concentrations throughout the cell cycle, but only Orc2 was stably bound to chromatin. Orc1 and Mcm3 were easily eluted from chromatin during mitosis and early G1 phase, but became stably bound during mid‐G1 phase, concomitant with the appearance of a functional pre‐replication complex at a hamster replication origin. Since hamster Orc proteins are closely related to their human and mouse homologs, the unexpected behavior of hamster Orc1 provides a novel mechanism in mammals for delaying assembly of pre‐replication complexes until mitosis is complete and a nuclear structure has formed.
BackgroundTissue acidosis is effective in causing chronic muscle pain. However, how muscle nociceptors contribute to the transition from acute to chronic pain is largely unknown.ResultsHere we showed that a single intramuscular acid injection induced a priming effect on muscle nociceptors of mice. The primed muscle nociceptors were plastic and permitted the development of long-lasting chronic hyperalgesia induced by a second acid insult. The plastic changes of muscle nociceptors were modality-specific and required the activation of acid-sensing ion channel 3 (ASIC3) or transient receptor potential cation channel V1 (TRPV1). Activation of ASIC3 was associated with increased activity of tetrodotoxin (TTX)-sensitive voltage-gated sodium channels but not protein kinase Cϵ (PKCϵ) in isolectin B4 (IB4)-negative muscle nociceptors. In contrast, increased activity of TTX-resistant voltage-gated sodium channels with ASIC3 or TRPV1 activation in NaV1.8-positive muscle nociceptors was required for the development of chronic hyperalgesia. Accordingly, compared to wild type mice, NaV1.8-null mice showed briefer acid-induced hyperalgesia (5 days vs. >27 days).ConclusionASIC3 activation may manifest a new type of nociceptor priming in IB4-negative muscle nociceptors. The activation of ASIC3 and TRPV1 as well as enhanced NaV1.8 activity are essential for the development of long-lasting hyperalgesia in acid-induced, chronic, widespread muscle pain.
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