DREAM Repression and Dynorphin Expression
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DREAM Repression and Dynorphin Expression
The experience of pain in response to noxious stimuli serves a crucial biological purpose: it alerts a living organism to environmental dangers, inducing behavioral responses that protect the organism from further damage. In contrast, chronic pain arising from disease states and/or pathological functioning of the nervous system offers no advantage and may be debilitating to those afflicted. Control and treatment of chronic pain remain major clinical challenges. The calcium-sensing protein DREAM (Downstream Regulatory Element Antagonistic Modulator) is a putative transcriptional repressor involved in modulating pain (Ref.1).

DREAM is constitutively expressed in certain neurons and transcriptional activity of the repressor DREAM depends on its high affinity binding to a DRE (Downstream Response Element) site in target genes, which is important in regulating the transcription of the endogenous opioid gene prodynorphin in spinal cord neurons in response to elevations of [Ca2+] I (Ref.2), blocking RNA Polymerase-II, and thereby transcription. The process is controlled by the levels of nuclear Ca2+, the PI3K (Phosphatidylinositol-3 Kinase) pathway or by a PKA (Protein Kinase-A)-mediated phosphorylation of CREM (cAMP Responsive Element Modulator). Three functional calcium chelating EF-hand motifs in the DREAM protein sense the intracellular concentration of Ca2+ and EF-hand occupancy by Ca2+ blocks binding of DREAM to DRE sites. Thus, the increased levels of intracellular Ca2+ following membrane depolarization or release from intracellular stores result in DREAM-mediated transcriptional derepression (Ref.3). Prodynophin transcription is also regulated by transactivators including CREB (cAMP Responsive Element Binding protein) binding to CRE (cAMP Response Element) consensus sites, and c-Fos with c-Jun to an Activating Protein-1 site. CREB activation and c-Fos levels are regulated by activity-dependent activation of PKA and ERK (Extracellular Signal-Regulated Kinase). At resting nuclear Ca2+ levels, DREAM is bound to DNA and suppresses transcription by preventing the interaction of transcription factors and coactivators such as CBP (CREB Binding Protein) or p300. These events occur in the nucleus, suggesting that inactivation of DREAM requires a nuclear Ca2+ elevation. The residues in DREAM and the downstream kinases in the PI3K pathway responsible for this are presently unknown.

By suppressing dynorphin levels in the spinal cord DREAM regulate pain transmission by controlling the level of kappa receptor activation, offering a new possibility for managing pain. Dynorphin is an endogenous ligand for the kappa Opiate Receptor, which, along with other receptors, is a member of the opiate GPCR (G-Protein Coupled Receptor) family. Agonists of these receptors are major candidate drugs for pain control (Ref.4). Other pleiotropic functions of DREAM are as varied as that of a transcription factor, a binding partner for presenilins, and a modulator of potassium channels.