The synapsins: Key actors of synapse function and plasticity (original) (raw)

The Role of Synapsins in Neurological Disorders

Neuroscience bulletin, 2018

Synapsins serve as flagships among the presynaptic proteins due to their abundance on synaptic vesicles and contribution to synaptic communication. Several studies have emphasized the importance of this multi-gene family of neuron-specific phosphoproteins in maintaining brain physiology. In the recent times, increasing evidence has established the relevance of alterations in synapsins as a major determinant in many neurological disorders. Here, we give a comprehensive description of the diverse roles of the synapsin family and the underlying molecular mechanisms that contribute to several neurological disorders. These physiologically important roles of synapsins associated with neurological disorders are just beginning to be understood. A detailed understanding of the diversified expression of synapsins may serve to strategize novel therapeutic approaches for these debilitating neurological disorders.

A Third Member of the Synapsin Gene Family

Proceedings of The National Academy of Sciences, 1998

Synapsins are a family of neuron-specific synaptic vesicle-associated phosphoproteins that have been implicated in synaptogenesis and in the modulation of neurotransmitter release. In mammals, distinct genes for synapsins I and II have been identified, each of which gives rise to two alternatively spliced isoforms. We have now cloned and characterized a third member of the synapsin gene family, synapsin III, from human DNA. Synapsin III gives rise to at least one protein isoform, designated synapsin IIIa, in several mammalian species. Synapsin IIIa is associated with synaptic vesicles, and its expression appears to be neuron-specific. The primary structure of synapsin IIIa conforms to the domain model previously described for the synapsin family, with domains A, C, and E exhibiting the highest degree of conservation. Synapsin IIIa contains a novel domain, termed domain J, located between domains C and E. The similarities among synapsins I, II, and III in domain organization, neuronspecific expression, and subcellular localization suggest a possible role for synapsin III in the regulation of neurotransmitter release and synaptogenesis. The human synapsin III gene is located on chromosome 22q12-13, which has been identified as a possible schizophrenia susceptibility locus. On the basis of this localization and the well established neurobiological roles of the synapsins, synapsin III represents a candidate gene for schizophrenia.

Synapsins: Mosaics of Shared and Individual Domains in a Family of Synaptic Vesicle Phosphoproteins

Science, 1989

Synapsins are neuronal phosphoproteins that coat synaptic vesicles, bind to the cytoskeleton, and are believed to function in the regulation of neurotransmitter release. Molecular cloning reveals that the synapsins comprise a family of four homologous proteins whose messenger RNA's are generated by differential splicing oftranscripts from two genes. Each synapsin is a mosaic composed of homologous amino-terminal domains common to all synapsins and different combinations of distinct carboxylterminal domains. Immunocytochemical studies demonstrate that all four synapsins are widely distributed in nerve terminals, but that their relative amounts vary among different kinds of synapses. The structural diversity and differential distribution of the four synapsins suggest common and different roles ofeach in the integration of distinct signal transduction pathways that modulate neurotransmitter release in various types of neurons. T HE RELEASE OF NEUROTRANSMITIERS IS THE FINAL COMmon pathway in all neuronal function. This release involves the Ca2+-dependent exocytosis of synaptic vesicles at the nerve terminal (1). Under various physiological conditions, membrane depolarization and neurotransmitter release at the nerve terminal are correlated with the phosphorylation of the synapsins (2). Synapsins are a group of four synaptic vesicle membrane proteins: synapsins Ia and Ib (collectively referred to as synapsin I) and synapsins IIa and lIb [originally named proteins IIIa and IIIb (2) and together referred to as synapsin II]. It has been suggested that synapsin I links synaptic vesicles to cytoskeletal elements in the presynaptic nerve terminal (3, 4) and regulates neurotransmitter release (5). Less is known about the

Synapsin III: Role in neuronal plasticity and disease

Seminars in Cell & Developmental Biology, 2011

Synapsin III was discovered in 1998, more than two decades after the first two synapsins (synapsins I and II) were identified. Although the biology of synapsin III is not as well understood as synapsins I and II, this gene is emerging as an important factor in the regulation of the early stages of neurodevelopment and dopaminergic neurotransmission, and in certain neuropsychiatric illnesses. Molecular genetic and clinical studies of synapsin III have determined that its neurodevelopmental effects are exerted at the levels of neurogenesis and axonogenesis. In vitro voltammetry studies have shown that synapsin III can control dopamine release in the striatum. Since dopaminergic dysfunction is implicated in many neuropsychiatric conditions, one may anticipate that polymorphisms in synapsin III can exert pervasive effects, especially since it is localized to extrasynaptic sites. Indeed, mutations in this gene have been identified in individuals diagnosed with schizophrenia, bipolar disorder and multiple sclerosis. These and other findings indicate that the roles of synapsin III differ significantly from those of synapsins I and II. Here, we focus on the unique roles of the newest synapsin, and where relevant, compare and contrast these with the actions of synapsins I and II.

The role of synapsins in neuronal development

Cellular and molecular …, 2010

The synapsins, the first identified synaptic vesicle-specific proteins, are phosphorylated on multiple sites by a number of protein kinases and are involved in neurite outgrowth and synapse formation as well as in synaptic transmission. In mammals, the synapsin family consists of at least 10 isoforms encoded by 3 distinct genes and composed by a mosaic of conserved and variable domains. The synapsins are highly conserved evolutionarily, and orthologues have been found in invertebrates and lower vertebrates. Within nerve terminals, synapsins are implicated in multiple interactions with presynaptic proteins and the actin cytoskeleton. Via these interactions, synapsins control several mechanisms important for neuronal homeostasis. In this review, we describe the main functional features of the synapsins, in relation to the complex role played by these phosphoproteins in neuronal development.

Synapsins: From synapse to network hyperexcitability and epilepsy

Seminars in Cell & Developmental Biology, 2011

The synapsin family in mammals consists of at least 10 isoforms encoded by three distinct genes and composed by a mosaic of conserved and variable domains. Synapsins, although not essential for the basic development and functioning of neuronal networks, are extremely important for the fine-tuning of SV cycling and neuronal plasticity.

The Synapsins and the Control of Neuroexocytosis

Molecular Biology Intelligence Unit, 2007

T he synapsins have been the first synaptic vesicle-associated proteins to be discovered thanks to their prominent ability to be phosphorylated by a variety of protein kinases. At present, the synapsin family in mammals consists of at least 10 isoforms encoded by three distinct genes and composed by a mosaic of conserved and variable domains. The synapsins are highly conserved evolutionarily and synapsin homologues have been described in invertebrates and lower vertebrates. The synapsins are implicated in multiple interactions with synaptic vesicle proteins and phospholipids, actin and protein kinases. Via these interactions, the synapsins play multiple roles in synaptic transmission, including control of synapse formation, regulation of synaptic vesicle trafficking and neurotransmitter release and expression of short-term synaptic plasticity phenomena. This chapter tries to summarize the main functional features of the synapsins that have emerged in the last 20 years, in order to provide a framework for interpreting the complex role played by these phosphoproteins in synaptic physiology.

A Phospho-Switch Controls the Dynamic Association of Synapsins with Synaptic Vesicles

Neuron, 1999

hypothesis, all synapsins bind ATP with high affinity † Department of Biochemistry Sü dhof, 1998a, 1998b). In addition to syn-Center for Basic Neuroscience aptic vesicles, synapsins bind to several proteins in vitro ‡ Howard Hughes Medical Institute (reviewed by . Most prominent among The University of Texas Southwestern these is actin, which binds to synapsins at multiple sites Medical School (Bahler and Greengard, 1987; Petrucci and Morrow, Dallas, Texas 75235 1987; Goold et al., 1995). However, nerve terminals contain relatively little actin compared with axons or postsynaptic densities, and synapsins can be completely Summary solubilized with detergents, while actin cannot. This suggests that synapsins bind to actin only transiently in Synapsins constitute a family of synaptic vesicle provivo and primarily serve as coat proteins on synaptic teins essential for regulating neurotransmitter release.

Suppression of synapsin II inhibits the formation and maintenance of synapses in hippocampal culture

Proceedings of the National Academy of Sciences, 1995

Numerous synaptic proteins, including several integral membrane proteins, have been assigned roles in synaptic vesicle fusion with or retrieval from the presynaptic plasma membrane. In contrast, the synapsins, neuron-specific phosphoproteins associated with the cytoplasmic surface of synaptic vesicles, appear to play a much broader role, being involved in the regulation of neurotransmitter release and in the organization of the nerve terminal. Here we have administered antisense synapsin II oligonucleotides to dissociated hippocampal neurons, either before the onset of synaptogenesis or 1 week after the onset of synaptogenesis. In both cases, synapsin II was no longer detectable within 24-48 h of treatment. After 5 days of treatment, cultures were analyzed for the presence of synapses by synapsin I and synaptophysin antibody labeling and by electron microscopy. Cultures in which synapsin II was suppressed after axon elongation, but before synapse formation, did not develop synapses. Cultures in which synapsin II was suppressed after the development of synapses lost most of their synapses. Remarkably, with the removal of the antisense oligonucleotides, neurons and their synaptic connections recovered. These studies lead us to conclude that synapsin II is involved in the formation and maintenance of synapses in hippocampal neurons.