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Solomon H Snyder

Publications and source records attributed to Solomon H Snyder.

At least 55 records · Page 3Linked to original sources
PubMed2004

Phospholipase C-gamma1 is a guanine nucleotide exchange factor for dynamin-1 and enhances dynamin-1-dependent epidermal growth factor receptor endocytosis.

Phospholipase C-gamma1 (PLC-gamma1), which interacts with a variety of signaling molecules through its two Src homology (SH) 2 domains and a single SH3 domain has been implicated in the regulation of many cellular functions. We demonstrate that PLC-gamma1 acts as a guanine nucleotide exchange factor (GEF) of dynamin-1, a 100 kDa GTPase protein, which is involved in clathrin-mediated endocytosis of epidermal growth factor (EGF) receptor. Overexpression of PLC-gamma1 increases endocytosis of the EGF receptor by increasing guanine nucleotide exchange activity of dynamin-1. The GEF activity of PLC-gamma1 is mediated by the direct interaction of its SH3 domain with dynamin-1. EGF-dependent activation of ERK and serum response element (SRE) are both up-regulated in PC12 cells stably overexpressing PLC-gamma1, but knockdown of PLC-gamma1 by siRNA significantly reduces ERK activation. These results establish a new role for PLC-gamma1 in the regulation of endocytosis and suggest that endocytosis of activated EGF receptors may mediate PLC-gamma1-dependent proliferation.

Animals↗
PubMed2004

Autophagosome-like vacuole formation in Huntington's disease lymphoblasts.

In an effort to clarify cellular abnormalities in Huntington's disease without the confounding factor of gross degeneration and postmortem alterations associated with studies of the brain, we have examined HD patient lymphoblasts. We report pronounced vacuole formation in patients. The vacuoles possess huntingtin remnants and cathepsin B staining, a lysosomal marker, suggesting autophagy. The number and size of vacuoles parallel the number of polyglutamine repeats in patients. Treatment with staurosporine, which augments apoptosis, leads to increased vacuole formation in Huntington's disease cells but does not influence control cells. Our findings provide direct evidence for abnormalities in Huntington's disease tissues outside the brain under basal conditions. Autophagic cellular alterations may be utilized as peripheral markers of Huntington's disease pathology.

Adult↗
PubMed2004

Heme oxygenase-2 is activated by calcium-calmodulin.

The heme oxygenase family of enzymes catalyzes the metabolism of heme to biliverdin, ferrous iron, and carbon monoxide (CO). At least two isoforms exist, heme oxygenase-1 (HO1) and heme oxygenase-2 (HO2), which are encoded by separate genes. HO2 is selectively enriched in neurons, and substantial evidence suggests that HO2-derived CO functions as a neurotransmitter/neuromodulator. However, a molecular mechanism for the rapid activation of HO2 during neuronal activity has not been described. Through a yeast two-hybrid screen we identified calmodulin as a potential regulator of HO2 activity. Calmodulin binds with nanomolar affinity to HO2 in a calcium-dependent manner via a canonical 1-10 motif, resulting in a 3-fold increase in catalytic activity. Mutations within this motif block calmodulin binding and calcium-dependent stimulation of enzyme activity in vitro and in intact cells. The calcium mobilizing agents ionomycin and glutamate stimulate endogenous HO2 activity in primary cortical cultures, establishing in vivo relevance. Calcium-calmodulin provides a mechanism for rapid and transient activation of HO2 during neuronal activity.

Animals↗
PubMed2004

Apoptosis and calcium: new roles for cytochrome c and inositol 1,4,5-trisphosphate.

Mounting evidence suggests that calcium released from internal stores plays a critical role in the progression of apoptosis. The primary calcium release channel on endoplasmic reticulum membranes is the inositol 1,4,5-trisphosphate receptor (IP3R). Deletion of the gene for IP3R results in defects in apoptosis in response to multiple stimuli. Conversely, augmented IP3R levels are associated with increased cell death. A mechanistic basis for altered IP3R function during apoptosis was revealed with the discovery that cytochrome c binds to IP3R early in apoptosis. This interaction blocks the calcium-dependent inhibition of IP3R function, resulting in increased calcium release from internal stores. The resultant cytoplasmic and mitochondrial calcium overload culminates in cell-wide cytochrome c release and maximal caspase activation. These findings highlight the importance of intracellular calcium stores in apoptosis, and the multi-functional role of cytochrome c released from mitochondria in cell death.

Animals↗
PubMed2004

Agonist-induced Ca2+ entry determined by inositol 1,4,5-trisphosphate recognition.

It has been considered that Ca2+ release is the causal trigger for Ca2+ entry after receptor activation. In DT40 B cells devoid of inositol 1,4,5-trisphosphate receptors (IP3R), the lack of Ca2+ entry in response to receptor activation is attributed to the absence of Ca2+ release. We reveal in this article that IP3R recognition of IP3 determines agonist-induced Ca2+ entry (ACE), independent of its Ca2+ release activity. In DT40 IP3R(-/-) cells, endogenous ACE can be rescued with type 1 IP3R mutants (both a DeltaC-terminal truncation mutant and a D2550A pore mutant), which are defective in Ca2+ release channel activity. Thus, in response to B cell receptor activation, ACE is restored in an IP3R-dependent manner without Ca2+ store release. Conversely, ACE cannot be rescued with mutant IP3Rs lacking IP3 binding (both the Delta90-110 and R265Q IP3-binding site mutants). We conclude that an IP3-dependent conformational change in the IP3R, not endoplasmic reticulum Ca2+ pool release, triggers ACE.

Amino Acid Substitution↗
PubMed2004

RACK1 binds to inositol 1,4,5-trisphosphate receptors and mediates Ca2+ release.

RACK1 is not a G protein but closely resembles the heterotrimeric Gbeta-subunit. RACK1 serves as a scaffold, linking protein kinase C to its substrates. We demonstrate that RACK1 physiologically binds inositol 1,4,5-trisphosphate receptors and regulates Ca2+ release by enhancing inositol 1,4,5-trisphosphate receptor binding affinity for inositol 1,4,5-trisphosphate. Overexpression of RACK1 or depletion of RACK1 by interference RNA markedly augments or diminishes Ca2+ release, respectively, without affecting Ca2+ entry. These findings establish RACK1 as a physiologic mediator of agonist-induced Ca2+ release.

Amino Acid Substitution↗
PubMed2004

Carbon monoxide mediates vasoactive intestinal polypeptide-associated nonadrenergic/noncholinergic neurotransmission.

Carbon monoxide (CO) synthesized by heme oxygenase 2 (HO2) and nitric oxide (NO) produced by neuronal NO synthase (nNOS) mediate nonadrenergic/noncholinergic (NANC) intestinal relaxation. In many areas of the gastrointestinal tract, NO and CO function as coneurotransmitters. In the internal anal sphincter (IAS), NANC relaxation is mediated primarily by CO. Vasoactive intestinal polypeptide (VIP) has also been shown to participate in NANC relaxation throughout the intestine, including the IAS. By using a combination of pharmacology and genetic knockout of the biosynthetic enzymes for CO and NO, we show that the physiologic effects of exogenous and endogenous VIP in the IAS are mediated by HO2-synthesized CO.

Anal Canal↗
PubMed2004

PIKE (phosphatidylinositol 3-kinase enhancer)-A GTPase stimulates Akt activity and mediates cellular invasion.

Akt/PKB is a crucial regulator of diverse cellular processes and contributes to cancer progression. Activation of Akt is essentially dependent on phosphatidylinositol (PI) 3-kinase signaling. Here, we describe a novel mediator of Akt that is independent of PI 3-kinase. This mediator, PIKE-A, is a PIKE isoform and contains GTPase, pleckstrin homology, ArfGAP, and ankyrin repeats domains. PIKE-A directly binds to activated Akt but not PI 3-kinase in a guanine nucleotide-dependent way and stimulates the kinase activity of Akt. Overexpression of PIKE-A enhances Akt activity and promotes cancer cell invasion, whereas dominant-negative PIKE-A and PIKE-A knockdown markedly inhibit these processes. Our results demonstrate that PIKE-A is a physiologic regulator of Akt and an oncogenic effector of cell invasion.

Cell Line, Tumor↗
PubMed2004

PIKE GTPase: a novel mediator of phosphoinositide signaling.

Phosphoinositide (PI) 3-kinase enhancer (PIKE) is a brain-specific GTPase that binds to PI 3-kinase and stimulates its lipid kinase activity. It exists in two forms: the first to be identified, PIKE-S, is shorter and exclusively nuclear; by contrast, the longer form, PIKE-L, resides in multiple intracellular compartments. Nerve growth factor treatment leads to PIKE-S activation by triggering the nuclear translocation of phospholipase C (PLC)-gamma 1, which acts as a physiological guanine nucleotide exchange factor (GEF) for PIKE-S through its Src-homology 3 (SH3) domain. Cytoplasmic PI 3-kinase and its lipid product phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P3] regulate the membrane translocation and activation of many signaling molecules by binding to their pleckstrin homology (PH) domains. However, little is known about the physiological roles of their nuclear counterparts. The nuclear PLC-gamma 1/PIKE-S/PI 3-kinase signaling pathway seems to be an extension of the crosstalk between cytoplasmic PLC-gamma 1 and PI 3-kinase. PIKE-L contains a C-terminal extension consisting of an ADP ribosylation-GTPase-activating protein (ArfGAP) domain and two ankyrin repeats in addition to the N-terminal GTPase domain. PIKE-L could have additional, extranuclear functions, including regulation of postsynaptic signaling by metabotropic glutamate receptors.

Brain↗
PubMed2004

Opiate receptors and beyond: 30 years of neural signaling research.

Identification of opiate receptors some 30 years ago provided tools that brought major new insights into how these drugs act and led to the discovery of a novel group of atypical neurotransmitters, the peptide enkephalins being the first. The ligand binding techniques that were used to identify opiate receptors were employed to characterize receptors for all of the major neurotransmitters in the brain leading to additional insights into the actions of many drugs, such as neuroleptics. These techniques also permitted characterization of intracellular signaling systems such as the IP3 receptor and immunophilins. Even more novel than the enkephalins have been the gaseous neurotransmitters NO and CO and D-serine.

Animals↗
PubMed2004

D-Serine as a putative glial neurotransmitter.

Abundant recent evidence favors a neurotransmitter/neuromodulator role for D-serine. D-serine is synthesized from L-serine by serine racemase in astrocytic glia that ensheath synapses, especially in regions of the brain that are enriched in NMDA-glutamate receptors. D-serine is more potent than glycine at activating the 'glycine' site of these receptors. Moreover, selective degradation of D-serine but not glycine by D-amino acid oxidase markedly reduces NMDA neurotransmission. D-serine appears to be released physiologically in response to activation by glutamate of AMPA-glutamate receptors on D-serine-containing glia. This causes glutamate-receptor-interacting protein, which binds serine racemase, to stimulate enzyme activity and D-serine release. Thus, glutamate triggers the release of D-serine so that the two amino acids can act together on postsynaptic NMDA receptors. D-serine also plays a role in neural development, being released from Bergmann glia to chemokinetically enhance the migration of granule cell cerebellar neurons from the external to the internal granular layer.

Journal Article↗
PubMed2004

Inositol 1,4,5-trisphosphate receptors as signal integrators.

The inositol 1,4,5 trisphosphate (IP3) receptor (IP3R) is a Ca2+ release channel that responds to the second messenger IP3. Exquisite modulation of intracellular Ca2+ release via IP3Rs is achieved by the ability of IP3R to integrate signals from numerous small molecules and proteins including nucleotides, kinases, and phosphatases, as well as nonenzyme proteins. Because the ion conduction pore composes only approximately 5% of the IP3R, the great bulk of this large protein contains recognition sites for these substances. Through these regulatory mechanisms, IP3R modulates diverse cellular functions, which include, but are not limited to, contraction/excitation, secretion, gene expression, and cellular growth. We review the unique properties of the IP3R that facilitate cell-type and stimulus-dependent control of function, with special emphasis on protein-binding partners.

Adenosine Triphosphate↗
PubMed2003

Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosis.

Mitochondrial cytochrome c release and inositol (1,4,5) trisphosphate receptor (InsP(3)R)-mediated calcium release from the endoplasmic reticulum mediate apoptosis in response to specific stimuli. Here we show that cytochrome c binds to the InsP(3)R during apoptosis. Addition of 1 nM cytochrome c blocks calcium-dependent inhibition of InsP(3)R function. Early in apoptosis, cytochrome c translocates to the endoplasmic reticulum where it selectively binds InsP(3)R, resulting in sustained, oscillatory cytosolic calcium increases. These calcium events are linked to the coordinate release of cytochrome c from all mitochondria. Our findings identify a feed-forward mechanism whereby early cytochrome c release increases InsP(3)R function, resulting in augmented cytochrome c release that amplifies the apoptotic signal.

Animals↗
PubMed2003

PI3 kinase enhancer-Homer complex couples mGluRI to PI3 kinase, preventing neuronal apoptosis.

Phosphoinositide 3 kinase enhancer (PIKE) is a recently identified nuclear GTPase that activates nuclear phosphoinositide 3-kinase (PI3 kinase). We have identified, cloned and characterized a new form of PIKE, designated PIKE-L, which, unlike the nuclear PIKE-S, localizes to both the cytoplasm and the nucleus. We demonstrate physiologic binding of PIKE-L to Homer, an adaptor protein known to link metabotropic glutamate receptors to multiple intracellular targets including the inositol 1,4,5-trisphosphate receptor (IP3R). We show that activation of group I metabotropic glutamate receptors (mGluRIs) enhances formation of an mGluRI-Homer-PIKE-L complex, leading to activation of PI3 kinase activity and prevention of neuronal apoptosis. Our findings indicate that this complex mediates the well-known ability of agonists of mGluRI to prevent neuronal apoptosis.

Adenoviridae↗
PubMed2003

Carbon monoxide neurotransmission activated by CK2 phosphorylation of heme oxygenase-2.

Carbon monoxide (CO) is a putative gaseous neurotransmitter that lacks vesicular storage and must be synthesized rapidly following neuronal depolarization. We show that the biosynthetic enzyme for CO, heme oxygenase-2 (HO2), is activated during neuronal stimulation by phosphorylation by CK2 (formerly casein kinase 2). Phorbol ester treatment of hippocampal cultures results in the phosphorylation and activation of HO2 by CK2, implicating protein kinase C (PKC) in CK2 stimulation. Odorant treatment of olfactory receptor neurons augments HO2 phosphorylation and activity as well as cyclic guanosine monophosphate (cGMP) levels, with all of these effects selectively blocked by CK2 inhibitors. Likewise, CO-mediated nonadrenergic, noncholinergic (NANC) relaxation of the internal anal sphincter requires CK2 activity. Our findings provide a molecular mechanism for the rapid neuronal activation of CO biosynthesis, as required for a gaseous neurotransmitter.

Animals↗
PubMed2003

Akt as a mediator of cell death.

Protein kinase B/Akt possesses prosurvival and antiapoptotic activities and is involved in growth factor-mediated neuronal protection. In this study we establish Akt deactivation as a causal mediator of cell death. Akt deactivation occurs in multiple models of cell death including N-methyl-d-aspartate excitotoxicity, vascular stroke, and nitric oxide (NO)- and hydrogen peroxide (H2O2)-elicited death of HeLa, PC12, and Jurkat T cells. Akt deactivation characterizes both caspase-dependent and -independent cell death. Conditions rescuing cell death, such as treatment with poly(ADP-ribose) polymerase or NO synthase inhibitors and preconditioning with sublethal concentrations of N-methyl-d-aspartate, restore Akt activity. Infection of neurons with adenovirus expressing constitutively active Akt prevents excitotoxicity, whereas phosphatidylinositol 3-kinase inhibitors or infection with dominant negative Akt induce death of untreated neuronal cells.

Animals↗