Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Persistent hyperalgesia is associated with increased expression of proteins that contribute to enhanced excitability of spinal neurons, however, little is known about how expression of these proteins is regulated. We tested the hypothesis that Substance P stimulation of neurokinin receptors on spinal neurons activates the transcription factor nuclear factor of activated T cells isoform 4 (NFATc4). The occurrence of NFATc4 in spinal cord was demonstrated with RT-PCR and immunocytochemistry. Substance P activated NFAT-dependent gene transcription in primary cultures of neonatal rat spinal cord transiently transfected with a luciferase DNA reporter construct. The effect of Substance P was mediated by neuronal neurokinin-1 receptors that coupled to activation of protein kinase C, l-type voltage-dependent calcium channels, and calcineurin. Interestingly, Substance P had no effect on cyclic AMP response element (CRE)-dependent gene expression. Conversely, calcitonin gene-related peptide, which activated CRE-dependent gene expression, did not activate NFAT signaling. These data provide evidence that peptides released from primary afferent neurons regulate discrete patterns of gene expression in spinal neurons. Because the release of Substance P and calcitonin gene-related peptide from primary afferent neurons is increased following peripheral injury, these peptides may differentially regulate the expression of proteins that underlie persistent hyperalgesia.
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PMID:Substance P initiates NFAT-dependent gene expression in spinal neurons. 1653 71

Calcineurin may be involved in affecting nociceptive processes in multiple circumstances. It is conceivable that interfering with calcineurin's normal role in contributing to glial resting membrane potential, via its effects on the ion channel (TRESK) [tandem-pore-domain weakly inward rectifying potassium channels (TWIK)-related spinal cord potassium channels] may facilitate nociception. Another aspect of calcineurin function may be its role in the pronociceptive signaling of nuclear factor of activated T-cells (NFAT). NFAT activation via mediators (e.g. Substance P, brain-derived neurotrophic factor, nerve growth factor, bradykinin) appears to be dependent on calcineurin function. This calcineurin-regulated NFAT signaling may subsequently lead to transcription of pronociceptive genes as well as upregulation of pronociceptive chemokine receptors in the dorsal root ganglion. In fact, multiple articles have described the clinical use of calcineurin-inhibitors leading to pain, a phenomenon referred to as calcineurin inhibitor-induced pain syndrome (CIPS). Thus, it appears that calcineurin functions may encompass actions which promote or dampen nociceptive processes. A greater understanding of the physiology of calcineurin, especially as it relates to modulating nociception may lead to the development of novel analgesic targets in attempts to optimally alleviate patient discomfort.
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PMID:Calcineurin as a nociceptor modulator. 1966 90