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PubMed1991

Ethanol has no effect on cAMP-dependent protein kinase-, protein kinase C-, or Ca(2+)-calmodulin-dependent protein kinase II-stimulated phosphorylation of highly purified substrates in vitro.

The actions of ethanol on kinase stimulated phosphorylation were examined using highly purified protein kinases and a variety of purified substrates. Ethanol (25-200 mM) failed to alter the phosphorylation of histone IIa and histone IIIs by cAMP-dependent protein kinase (PKA) and protein kinase C (PKC), respectively. Moreover, ethanol (25-200 mM) did not affect the phosphorylation of synapsin I by Ca(2+)-calmodulin-dependent protein kinase II (CAM kinase II). Finally, neither PKA nor PKC stimulated phosphorylation of the GABAA receptor (GABAA-R) was modulated by ethanol at any concentration of ethanol tested. These results suggest that ethanol, in pharmacological concentrations, has no direct actions on the ability of these kinases to catalyze the phosphorylation of specific substrate proteins. In particular, ethanol does not appear to directly influence GABAA-R phosphorylation by either PKA or PKC.

Animals↗
PubMed2007

Defining the dopamine transporter proteome by convergent biochemical and in silico analyses.

Monoamine transporters play a key role in neuronal signaling by mediating reuptake of neurotransmitters from the synapse. The function of the dopamine transporter (DAT), an important member of this family of transporters, is regulated by multiple signaling mechanisms, which result in altered cell surface trafficking of DAT. Protein-protein interactions are likely critical for this mode of transporter regulation. In this study, we identified proteins associated with DAT by immunoprecipitation (IP) followed by mass spectrometry. We identified 20 proteins with diverse cellular functions that can be classified as trafficking proteins, cytoskeletal proteins, ion channels and extracellular matrix-associated proteins. DAT was found to associate with the voltage-gated potassium channel Kv2.1 and synapsin Ib, a protein involved in regulating neurotransmitter release. An in silico analysis provided evidence for common transcriptional regulation of the DAT proteome genes. In summary, this study identified a network of proteins that are primary candidates for functional regulation of the DAT, an important player in mechanisms of mental disorders and drug addiction.

Animals↗
PubMed1996

Vesicle-associated proteins and calcium in nerve terminals of chick ciliary ganglia during development of facilitation.

1. The developmental appearance of synaptic vesicle-associated proteins and nerve terminal calcium ([Ca2+]i) sequestering processes were determined for the chick ciliary ganglia in relation to the maturation of the different phase of increased efficacy of transmitter release following nerve impulses. The maturation phases studied were from stages 34-35, at the time of synapse formation, to stage 46 at hatching. 2. Western blots and immunohistochemical localization indicated that synaptotagmin 1 and synapsin IIa were detectable at stages 34-35 and were clearly localized at the nerve terminals by stage 37. Syntaxin was clearly localized at the nerve terminals at stage 34. 3. The relative size of the postganglionic compound action potential, used to measure the transmission efficacy through the ganglion, showed that the slope of the relationship between log efficacy and log extracellular calcium concentration ([Ca2+]o) in low [Ca2+]o was about 4 by stage 46. 4. A mature facilitatory mechanism for transmission was not present at stage 34 and did not emerge until stage 38. A mature augmentation was not present at stages 34 or 38 and was not established until stages 41-42. Post-tetanic potentiation (PTP) was not present at stage 34; it was evident at stages 37-38 and only reached maturity by stages 41-42. 5. The time course of calcium changes in the nerve terminals following trains of impulses that give rise to facilitation, augmentation and PTP was determined for different stages of development using the indicator Calcium Green-1 in the nerve terminal. The mature time course of the phases of calcium decline in the nerve terminal associated with facilitation and augmentation was observed as early as stage 38, whereas that of the PTP phase did not mature until after stage 42. 6. These results are discussed in terms of the maturation of the vesicle-associated proteins and calcium influx into the terminal following trains of impulses that give rise to the different components of increased synaptic efficacy.

Animals↗
PubMed2002

Neuron-specific expression of human angiotensinogen in brain causes increased salt appetite.

The brain renin-angiotensin system (RAS) has an important role in the regulation of cardiovascular function. In the brain, angiotensinogen (AGT) is expressed mainly in astrocytes (glia) and in some neurons in regions controlling cardiovascular activities. Because of the inability to dissect the functional role of astrocyte- vs. neuron-derived AGT in vivo by pharmacological approaches, the exact role of neuron-derived AGT in the regulation of blood pressure (BP) and fluid and electrolyte balance remains unclear. Therefore, we generated a transgenic mouse model overexpressing human AGT under the control of a neuron-specific (synapsin I) promoter (SYN-hAGT). These mice exhibited high-level expression of human AGT mRNA in the brain, with lower expression in the kidney and heart. Human AGT was not detected in plasma, but in the brain it was expressed exclusively in neurons. Intracerebroventricular (30 ng) but not intravenous (500 ng) injection of purified human renin (hREN) caused a pressor response, which was prevented by intracerebroventricular preinjection of the angiotensin II type 1 receptor antagonist losartan, indicating an AT(1) receptor-dependent functional role of neuron-derived AGT in the regulation of BP in response to exogenous REN. Double transgenic mice expressing both the hREN gene and SYN-hAGT transgene exhibited normal BP and water intake but had an increased preference for salt. These data suggest that neuronal AGT may play an important role in regulating salt intake and salt appetite.

Angiotensinogen↗
PubMed2002

Development of neural tissue and airway smooth muscle in fetal mouse lung explants: a role for glial-derived neurotrophic factor in lung innervation.

We have characterized the distribution of neural tissue and its primary target tissue, airway smooth muscle (ASM), in an in vitro mouse model of early lung development comprising left lung lobes at embryonic Day 12, cultured for 2 or 5 d. Neural tissue was detected with antibodies to protein gene product 9.5 (PGP 9.5), synapsin, and p75NTR (the low-affinity neurotrophin receptor), and smooth muscle with an antibody to alpha-actin. Imaging by confocal microscopy revealed few PGP 9.5-positive neurons at the start of culture; after 2 d clusters of neurons and nerve fibers had appeared along the lobar bronchus and after 5 d along the secondary and tertiary branches. Neural tissue did not just follow the smooth muscle-covered tubules, as seen in vivo, but also grew outside the lobes onto a wide layer of alpha-actin-positive cells, suggesting that smooth muscle may express a trophic factor that attracts nerves. Explants cultured with glial-derived neurotrophic factor (GDNF) exhibited a striking increase in the amount of p75NTR- and PGP 9.5-positive tissue outside the lobes, whereas GDNF-impregnated beads attracted neuronal precursors and influenced the direction of neurite extension. We show that the mouse lung explant is suitable for investigating trophic signals involved in pulmonary innervation and that GDNF may have a role in the early innervation of the developing airways.

Actins↗
PubMed1997

Dde-I restriction endonuclease fragmentation: a novel method of generating cDNA probes for in situ hybridization in brain.

We present a novel procedure for detection of low- and high-abundance messenger RNAs in the brain by in situ hybridization histochemistry, by using fragmented double-stranded cDNA as molecular probes. The procedure involves digesting the cDNA of interest with the restriction endonuclease from Desulfocibrio desulfuricans (Dde I digestion), followed by random primed labeling, which generates a family of high specific activity cDNA fragments. This procedure is a rapid, straightforward, and reproducible method of obtaining sensitive probes for in situ hybridization and is generally applicable to the analysis of the expression of a large number of genes. Here we report the use of this procedure to prepare probes for the detection of synapsin I, p150Glued, neurotensin, c-fos, and c-jun mRNAs in brain, using both isotopic and non-isotopic labeling methods. Because this procedure does not require complex recombinant DNA manipulations or oligonucleotide design, it should prove useful to the non-molecular biologist examining the expression of genes in the central nervous system.

Animals↗
PubMedDate not supplied

Reinnervation of isolated islets of Langerhans transplanted beneath the kidney capsule in the rat.

Neural regulation of islets of Langerhans mediates responses to stress and food ingestion. Transplantation of isolated islets offers hope to patients with insulin dependent diabetes mellitus but denervation of isolated islets may affect the capacity for appropriate metabolic control. Previous examination of the endocrine response to stress in islet autografted dogs revealed differences consistent with loss of neural regulation. Therefore, in the present study, islets grafted in rats were examined for extent and nature of reinnervation. Islets isolated from syngeneic donors were grafted under the kidney capsule of Wistar-Furth rats (n = 7) after 3 wk of streptozotocin induced diabetes. After 4 mo, graft-bearing kidneys were recovered and processed for double immunofluorescence. Antibodies were directed against (a) neuron associated proteins: synapsin (SYN) and L1; (b) neurotransmitters; tyrosine hydroxylase (TH), neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), and calcitonin gene-related peptide (CGRP); and (c) islet hormones: insulin and somatostatin. SYN and L1 immunoreactivities in nerve fibres suggested reinnervation of the grafted islets although fibres were not associated with structures within the transplanted islets as in intact islets. CGRP immunoreactivity was observed in fibres and in a subpopulation of cells within intact islets but only in cells of the grafted islets. VIP, TH, and NPY immunoreactivities were found in nerve fibres of intact islets but only VIP was observed in fibres of grafted islets suggesting an absence of sympathetic reinnervation. In conclusion, transplanted islets of Langerhans become reinnervated but with a distribution and complement of neurotransmitters distinct from intact islets.

Animals↗
PubMed2006

Reduction in the number of astrocytes and their projections is associated with increased synaptic protein density in the hypothalamus of poorly controlled diabetic rats.

Processes under hypothalamic control, such as thermogenesis, feeding behavior, and pituitary hormone secretion, are disrupted in poorly controlled diabetes, but the underlying mechanisms are poorly understood. Because glial cells regulate neurosecretory neurons through modulation of synaptic inputs and function, we investigated the changes in hypothalamic glia in rats with streptozotocin-induced diabetes mellitus. Hypothalamic glial fibrillary acidic protein (GFAP) levels decreased significantly 6 wk after diabetes onset. This was coincident with decreased GFAP immunoreactive surface area, astrocyte number, and the extension of GFAP immunoreactive processes/astrocyte in the arcuate nucleus. Cell death, analyzed by terminal deoxyuridine 5-triphosphate nick-end labeling and ELISA, increased significantly at 4 wk of diabetes. Proliferation, measured by Western blot for proliferating cell nuclear antigen and immunostaining for phosphorylated histone H-3, decreased in the hypothalamus of diabetic rats throughout the study, becoming significantly reduced by 8 wk. Both proliferation and death affected astroctyes because both phosphorylated histone H-3- and terminal deoxyuridine 5-triphosphate nick-end labeling-labeled cells were GFAP positive. Western blot analysis revealed that postsynaptic density protein 95 and the presynaptic proteins synapsin I and synaptotagmin increased significantly at 8 wk of diabetes, suggesting increased hypothalamic synaptic density. Thus, in poorly controlled diabetic rats, there is a decrease in the number of hypothalamic astrocytes that is correlated with modifications in synaptic proteins and possibly synaptic inputs. These morphological changes in the arcuate nucleus could be involved in neurosecretory and metabolic changes seen in diabetic animals.

Animals↗
PubMed2001

Targeted protein kinase A and PP-2B regulate insulin secretion through reversible phosphorylation.

Protein kinases and phosphatases play key roles in integrating signals from various insulin secretagogues. In this study, we show that the activities of the cAMP-dependent protein kinase (PKA) and the calcium/calmodulin-dependent phosphatase, PP-2B are coordinated resulting in the regulation of insulin secretion. Transient inhibition of PP-2B, using the immunosuppressant FK506, increased forskolin stimulated insulin secretion by 2.5-fold +/- 0.3 (n = 6) in rat islets and RINm5F cells. Surprisingly, forskolin treatment resulted in the dephosphorylation of the vesicle-associated protein synapsin 1 and increased PP-2B activity by 2.98 +/- 0.97-fold (n = 4). One potential explanation for the observed coordination of PKA and PP-2B activity is their colocalization through a mutual anchoring protein, AKAP79/150. Accordingly, RINm5F cells expressing AKAP79 exhibited decreased insulin secretion, reduced PP-2B activity and were insensitive to FK506. This suggests that AKAP targeting of PKA and PP-2B maintains a signal transduction complex that may regulate reversible phosphorylation events involved in insulin secretion.

Animals↗
PubMed1993

The 270 kDa splice variant of erythrocyte beta-spectrin (beta I sigma 2) segregates in vivo and in vitro to specific domains of cerebellar neurons.

Spectrin isoforms arise from four distinct genes, three of which generate multiple alternative transcripts. With no biochemical restrictions on the assembly of alpha beta heterodimers, more than 25 distinct heterodimeric spectrin species may exist. Whether (and why) this subtle but substantial diversity is realized in any single cell is unknown. To address this question, sequence-specific antibodies to alternatively spliced regions of alpha- and beta-spectrin have been prepared. Reported here is the localization in rat cerebellar neurons at light and electron microscopic levels of an antibody against a unique sequence (beta I sigma 2-A = PGQHKDGQKSTGDERPT) from the 270 kDa transcript of the red cell beta-spectrin gene (spectrin beta I sigma 2). In this version, the 3' sequence of erythroid beta-spectrin (beta I sigma 1) is replaced with an alternative sequence that shares substantial homology with the 3' sequence of non-erythroid beta-spectrin (beta II sigma 1). The antibody to beta I sigma 2-A stains a single protein band at 270 kDa, determined by western blotting, in both rat cerebellum and in cultured cerebellar granule cells, and does not react with beta II sigma 1 spectrin (beta-fodrin). This antibody stains the dendritic spines of Purkinje cells in the molecular layer, and is concentrated at postsynaptic densities (PSDs) adjacent to synapsin I (which is confined to the presynaptic membrane). The soma of Purkinje cells do not stain. In the granular layer, cytoplasmic organelles and the postsynaptic densities of granular cells stain strongly. Astrocytes are also stained. In all cells, plasma membrane staining is confined to postsynaptic densities (PSD). The beta I sigma 2 isoform co-immunoprecipitates with non-erythroid alpha-spectrin (alpha II sigma), even though the distribution of alpha II sigma within neurons only partially overlaps that of beta I sigma 2. No hybrid beta I sigma 2 and beta II sigma 1 (beta-fodrin) spectrin complexes appear to exist. Spectrin beta I sigma 2 is also polarized in cultured rat cerebellar granule cells, where it is abundant in cell bodies but not neurites. The overall distribution of beta I sigma 2 is as a subset of the distribution of spectrins 240/235E previously detected with a generally reactive erythrocyte alpha beta-spectrin antibody. These findings establish the highly precise segregation of a beta-spectrin isoform to distinct cytoplasmic and membrane surface domains, indicate that it is complexed (partially) with non-erythroid alpha-spectrin, and demonstrate that cytoskeletal targeting mechanisms are preserved in cultured granular cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed2004

Dopaminergic and serotonergic innervation of cockroach salivary glands: distribution and morphology of synapses and release sites.

The paired salivary glands in the cockroach are composed of acini with ion-transporting peripheral P-cells and protein-secreting central C-cells, and a duct system for the modification of the primary saliva. Secretory activity is controlled by serotonergic and dopaminergic neurons, whose axons form a dense plexus on the glands. The spatial relationship of release sites for serotonin and dopamine to the various cell types was determined by anti-synapsin immunofluorescence confocal microscopy and electron microscopy. Every C-cell apparently has only serotonergic synapses on its surface. Serotonergic and dopaminergic fibres on the acini have their release zones at a distance of approximately 0.5 microm from the P-cells. Nerves between acinar lobules may serve as neurohaemal organs and contain abundant dopaminergic and few serotonergic release sites. Some dopaminergic and serotonergic release sites reside in the duct epithelium, the former throughout the duct system, the latter only in segments next to acini. These findings are consistent with the view that C-cells respond exclusively to serotonin, P-cells to serotonin and dopamine, and most duct cells only to dopamine. Moreover, the data suggest that C-cells are stimulated by serotonin released close to their surface, whereas P-cells and most duct cells are exposed to serotonin/dopamine liberated at some distance.

Animals↗
PubMed2000

Effects of S-nitroso-cysteine on proteins that regulate exocytosis in PC12 cells: inhibitory effects on translocation of synaptophysin and ADP-ribosylation of GTP-binding proteins.

S-Nitroso-cysteine (SNC) inhibits Ca2+-induced noradrenaline (NA) release from PC12 cells. Since SNC stimulated Ca2+ mobilization from intracellular Ca2+ pools and SNC-induced inhibition of NA release was not washed-out, SNC may modify exocytosis-related proteins that overcome Ca2+ mobilization. In the present study, we investigated the effects of SNC on exocytosis-related proteins in PC12 cells. Ionomycin stimulated NA release and increased the immunoreactivity of synaptophysin in the cytosol fraction. A 25-kDa synaptosome-associated protein (SNAP-25), which localizes to plasma membranes and vesicles, increased in the cytosol fraction after stimulation. The increases in these proteins by ionomycin were inhibited in PC12 cells treated with 0.6 mM SNC. Synaptobrevin and synapsin-1 in the cytosol fraction, and syntaxin and 43 kDa growth-associated protein in the membrane fraction were not affected by ionomycin or SNC. Incubation of each protein with SNC did not affect antibody immunoreactivity. [32P]ADP-ribosylation of GTP-binding proteins (Gi/Go) by pertussis toxin, but not Gs by cholera toxin, was inhibited in SNC-treated PC12 cells and by co-addition of SNC to the assay mixture. These findings suggest that 1) SNC inhibits translocation of vesicles containing synaptophysin and SNAP-25, and 2) SNC reacts with cysteine residues in Gi/Go, causing inhibition of ADP-ribosylation by pertussis toxin.

ADP-Ribosylation Factors↗
PubMed2005

Improved Golgi-like visualization in retrogradely projecting neurons after EGFP-adenovirus infection in adult rat and monkey.

An adenovirus vector was generated using a neuron-specific promoter synapsin I and enhanced green fluorescent protein (EGFP) reporter (AdSynEGFP). In addition, two modifications were identified that resulted in robust and reliable retrograde transport and EGFP expression after injection of the virus into three different brain regions in adult rats (medial prefrontal cortex, posterior thalamic nuclear group, and CA1). These are postinjection survival times of 14 days and addition of high concentrations of NaCl (>or=600 mM) to the injection buffer. These modifications resulted in obvious improvement in the intensity of the EGFP signal and in the number of labeled cells. Use of anti-EGFP in immunofluorescence or immunoperoxidase processing further enhanced the signal so that Golgi-like filling of dendritic spines and axon collaterals was routinely achieved. Effectiveness of the AdSynEGFP for Golgi-like filling was confirmed in one rhesus monkey with injections in visual area V4. Because of the long-term viability of the infected neurons (at least up to 28 days in rats and 22 days in monkey), this AdSynEGFP is suitable for use in microcircuitry studies in combination with other fluorescently tagged elements, including anterogradely labeled extrinsic projections. The native EGFP signal (without antibody enhancement) may be sufficient for studies involving cultured cells or slices.

Adenoviridae↗
PubMed2006

Local sharing as a predominant determinant of synaptic matrix molecular dynamics.

Recent studies suggest that central nervous system synapses can persist for weeks, months, perhaps lifetimes, yet little is known as to how synapses maintain their structural and functional characteristics for so long. As a step toward a better understanding of synaptic maintenance we examined the loss, redistribution, reincorporation, and replenishment dynamics of Synapsin I and ProSAP2/Shank3, prominent presynaptic and postsynaptic matrix molecules, respectively. Fluorescence recovery after photobleaching and photoactivation experiments revealed that both molecules are continuously lost from, redistributed among, and reincorporated into synaptic structures at time-scales of minutes to hours. Exchange rates were not affected by inhibiting protein synthesis or proteasome-mediated protein degradation, were accelerated by stimulation, and greatly exceeded rates of replenishment from somatic sources. These findings indicate that the dynamics of key synaptic matrix molecules may be dominated by local protein exchange and redistribution, whereas protein synthesis and degradation serve to maintain and regulate the sizes of local, shared pools of these proteins.

Animals↗
PubMed2003

p53 is present in synapses where it mediates mitochondrial dysfunction and synaptic degeneration in response to DNA damage, and oxidative and excitotoxic insults.

A form of programmed cell-death called apoptosis occurs in neurons during development of the nervous system, and may also occur in a variety of neuropathological conditions. Here we present evidence obtained in studies of adult mice and neuronal cell cultures showing that p53 protein is present in synapses where its level and amount of phosphorylation are increased following exposure of the cells to the DNA-damaging agent etoposide. We also show that levels of active p53 increase in isolated cortical synaptosomes exposed to oxidative and excitotoxic insults. Increased levels of p53 also precede loss of synapsin I immunoreactive terminals in cultured hippocampal neurons exposed to etoposide. Synaptosomes from p53-deficient mice exhibit increased resistance to oxidative and excitotoxic insults as indicated by stabilization of mitochondrial membrane potential and decreased production of reactive oxygen species. Finally, we show that a synthetic inhibitor of p53 (PFT-alpha) protects synaptosomes from wild-type mice against oxidative and excitotoxic injuries, and preserves presynaptic terminals in cultured hippocampal neurons exposed to etoposide. Collectively, these findings provide the first evidence for a local transcription-independent action of p53 in synapses, and suggest that such a local action of p53 may contribute to the dysfunction and degeneration of synapses that occurs in various neurodegenerative disorders.

Animals↗
PubMed2006

Regulation of dendritic branching and spine maturation by semaphorin3A-Fyn signaling.

A member of semaphorin family, semaphorin3A (Sema3A), acts as a chemorepellent or chemoattractant on a wide variety of axons and dendrites in the development of the nervous systems. We here show that Sema3A induces clustering of both postsynaptic density-95 (PSD-95) and presynaptic synapsin I in cultured cortical neurons without changing the density of spines or filopodia. Neuropilin-1 (NRP-1), a receptor for Sema3A, is present on both axons and dendrites. When the cultured neurons are exposed to Sema3A, the cluster size of PSD-95 is markedly enhanced, and an extensive colocalization of PSD-95 and NRP-1 or actin-rich protrusion is seen. The effects of Sema3A on spine morphology are blocked by PP2, an Src type tyrosine kinase inhibitor, but not by the PP3, the inactive-related compound. In the cultured cortical neurons from fyn(-/-) mice, dendrites bear few spines, and Sema3A does not induce PSD-95 cluster formation on the dendrites. Sema3A and its receptor genes are highly expressed during the synaptogenic period of postnatal days 10 and 15. The cortical neurons in layer V, but not layer III, show a lowered density of synaptic bouton-like structure on dendrites in sema3A- and fyn-deficient mice. The neurons of the double-heterozygous mice show the lowered spine density, whereas those of single heterozygous mice show similar levels of the spine density as the wild type. These findings suggest that the Sema3A signaling pathway plays an important role in the regulation of dendritic spine maturation in the cerebral cortex neurons.

Actins↗
PubMed2002

Inflammation-dependent cerebral deposition of serum amyloid a protein in a mouse model of amyloidosis.

The major pathological hallmark of amyloid diseases is the presence of extracellular amyloid deposits. Serum amyloid A (SAA) is an apolipoprotein primarily produced in the liver. Serum protein levels can increase one thousandfold after inflammation. SAA is the precursor to the amyloid A protein found in deposits of systemic amyloid A amyloid (AA or reactive amyloid) in both mouse and human. To study the factors necessary for cerebral amyloid formation, we have created a transgenic mouse that expresses the amyloidogenic mouse Saa1 protein in the brain. Using the synapsin promoter to drive expression of the Saa1 gene, the brains of transgenic mice expressed both RNA and protein. Under noninflammatory conditions, transgenic mice do not develop AA amyloid deposits in the brain; however, induction of a systemic acute-phase response in transgenic mice enhanced amyloid deposition. This deposition was preceded by an increase in cytokine levels in the brain, suggesting that systemic inflammation may be a contributing factor to the development of cerebral amyloid. The nonsteroidal anti-inflammatory agent indomethacin reduced inflammation and protected against the deposition of AA amyloid in the brain. These studies indicate that inflammation plays an important role in the process of amyloid deposition, and inhibition of inflammatory cascades may attenuate amyloidogenic processes, such as Alzheimer's disease.

Age Factors↗
PubMed2002

Spatial and temporal regulation of Ca2+/calmodulin-dependent protein kinase II activity in developing neurons.

We have studied Ca2+/calmodulin-dependent protein kinase II (CaMKII) isoform distribution and activity in embryonic hippocampal neurons developing in culture. We have found a strong correlation between the expression of the alpha subunit of the enzyme and the ability to undergo depolarization-dependent phosphorylation, which in young neurons is limited to the somatodendritic pool of the kinase. The lack of responsiveness of the axons of young alphaCaMKII-positive neurons is not caused by a lower Ca2+ influx but rather by a differential balance between kinase and phosphatase activities in this compartment. After the establishment of synaptic contacts, the presynaptic pool of the kinase displays an increasing level of activity and acquires the parallel ability to phosphorylate synapsin I, which represents one of the major CaMKII presynaptic targets in mature nerve terminals. In contrast, the activity of the postsynaptic pool of the kinase remains constant throughout synaptogenesis. In the presence of a nearly homogeneous subcellular distribution, this highly regionalized regulation of activity may reflect the multifunctional roles of CaMKII in both developing and mature neurons.

Animals↗