Pro-apoptotic function of calsenilin/DREAM/KChIP3.
ABSTRACT Apoptotic cell death and increased production of amyloid b peptide (Ab) are pathological features of Alzheimer's disease (AD), although the exact contribution of apoptosis to the pathogenesis of the disease remains unclear. Here we describe a novel pro-apoptotic function of calsenilin/DREAM/KChIP3. By antisense oligonucleotide-induced inhibition of calsenilin/DREAM/KChIP3 synthesis, apoptosis induced by Fas, Ca2+-ionophore, or thapsigargin is attenuated. Conversely, calsenilin/DREAM/KChIP3 expression induced the morphological and biochemical features of apoptosis, including cell shrinkage, DNA laddering, and caspase activation. Calsenilin/DREAM/KChIP3-induced apoptosis was suppressed by caspase inhibitor Z-VAD and by Bcl-XL, and was potentiated by increasing cytosolic Ca2+, expression of Swedish amyloid precursor protein mutant (APPSW) or presenilin 2 (PS2), but not by a PS2 deletion lacking its C-terminus (PS2/411stop). In addition, calsenilin/DREAM/KChIP3 expression increased Ab42 production in cells expressing APPsw, which was potentiated by PS2, but not by PS2/411stop, which suggests a role for apoptosis-associated Ab42 production of calsenilin/DREAM/KChIP3.
Article: Distribution of downstream regulatory element antagonist modulator (DREAM) in rat spinal cord and upregulation of its expression during inflammatory pain.[show abstract] [hide abstract]
ABSTRACT: A previous knockout study revealed the critical role of downstream regulatory element antagonist modulator (DREAM) in pain processing in the spinal cord by transcriptional regulation of prodynorphin (PPD) gene. Here, we report that, in contrast to the nuclear localization of other transcription factors, DREAM showed a punctate staining pattern in rat spinal dorsal horn in immunofluorescent analysis, with a membrane localization profile in some neurons and its expression accumulated in the inner zone of lamina II. In an inflammatory pain model induced by complete Freund's adjuvant (CFA) injection, we used Western blot analysis and detected transient upregulation of DREAM in the nuclear fraction of ipsilateral spinal dorsal horn at 2 h and 6 h post-injection, and a slow upregulation in the membrane fraction for 7 days. These studies suggest that DREAM might have other roles in pain modulation in the spinal cord in addition to its well-known role as a transcriptional repressor.Neurochemical Research 10/2007; 32(9):1592-9. · 2.24 Impact Factor
Article: Expression and high glucose-mediated regulation of K+ channel interacting protein 3 (KChIP3) and KV4 channels in retinal Müller glial cells.[show abstract] [hide abstract]
ABSTRACT: Normal vision depends on the correct function of retinal neurons and glia and it is impaired in the course of diabetic retinopathy. Müller cells, the main glial cells of the retina, suffer morphological and functional alterations during diabetes participating in the pathological retinal dysfunction. Recently, we showed that Müller cells express the pleiotropic protein potassium channel interacting protein 3 (KChIP3), an integral component of the voltage-gated K(+) channels K(V)4. Here, we sought to analyze the role of KChIP3 in the molecular mechanisms underlying hyperglycemia-induced phenotypic changes in the glial elements of the retina. The expression and function of KChIp3 was analyzed in vitro in rat Müller primary cultures grown under control (5.6 mM) or high glucose (25 mM) (diabetic-like) conditions. We show the up-regulation of KChIP3 expression in Müller cell cultures under high glucose conditions and demonstrate a previously unknown interaction between the K(V)4 channel and KChIP3 in Müller cells. We show evidence for the expression of a 4-AP-sensitive transient outward voltage-gated K(+) current and an alteration in the inactivation of the macroscopic outward K(+) currents expressed in high glucose-cultured Müller cells. Our data support the notion that induction of KChIP3 and functional changes of K(V)4 channels in Müller cells could exert a physiological role in the onset of diabetic retinopathy.Biochemical and Biophysical Research Communications 01/2011; 404(2):678-83. · 2.48 Impact Factor
Article: The role of presenilin and its interacting proteins in the biogenesis of Alzheimer's beta amyloid.[show abstract] [hide abstract]
ABSTRACT: The biogenesis and accumulation of the beta amyloid protein (Abeta) is a key event in the cascade of oxidative and inflammatory processes that characterises Alzheimer's disease. The presenilins and its interacting proteins play a pivotal role in the generation of Abeta from the amyloid precursor protein (APP). In particular, three proteins (nicastrin, aph-1 and pen-2) interact with presenilins to form a large multi-subunit enzymatic complex (gamma-secretase) that cleaves APP to generate Abeta. Reconstitution studies in yeast and insect cells have provided strong evidence that these four proteins are the major components of the gamma-secretase enzyme. Current research is directed at elucidating the roles that each of these protein play in the function of this enzyme. In addition, a number of presenilin interacting proteins that are not components of gamma-secretase play important roles in modulating Abeta production. This review will discuss the components of the gamma-secretase complex and the role of presenilin interacting proteins on gamma-secretase activity.Neurochemical Research 04/2012; 32(4-5):609-23. · 2.24 Impact Factor