Synapsin I
Encyclopedia
Synapsin I, is the collective name for Synapsin Ia and Synapsin Ib, two nearly identical phosphoprotein
s that in humans are encoded by the SYN1 gene
. In its phosphorylated
form, Synapsin I may also be referred to as phosphosynaspin I. Synapsin I is the first of the proteins in the synapsin
family of phosphoproteins in the synaptic vesicles present in the central and peripheral nervous systems. Synapsin Ia and Ib are close in length and almost the same in make up, however, Synapsin Ib stops short of the last segment of the C-terminal in the amino acid sequence found in Synapsin Ia.
family that are neuronal phosphoprotein
s which associate with the cytoplasmic surface of synaptic vesicle
s. Family members are characterized by common protein domains, and they are implicated in synaptogenesis and the modulation of neurotransmitter
release, suggesting a potential role in several neuropsychiatric diseases.
The phosphoprotein plays a role in regulation of axonogenesis
and synaptogenesis
. The protein serves as a substrate for several different protein kinase
s and phosphorylation may function in the regulation of this protein in the nerve terminal.
Synapsin I is found in two isoforms of the protein, Synapsin Ia and Synapsin Ib, with Synapsin Ib being a slightly shorter version of the protein. Both Synapsin I proteins are highly basic with a pI
in the range of 10.3 and 10.2, respectively. Both isoforms are phosphorylated at identical locations within their protein sequences, specifically at the same three serine residues.
Synapsin I phosphoproteins make up approximately 6% of the total protein in synaptic vesicles. Among bovine, rat, and human it has been shown to be 95% homologous, with the central 'C' domain evolutionarily conserved. This phosphoprotein is loosely associated with the vesicular membrance and is easily dissociated by treatment with a salt, versus a detergent being required for its removal from the membrane.
Rich in the amino acids prorine and glycine, the compositional and structural natures of this protein are somewhat similar to collagen. This aided in the early determination of its structure using collagenase, and which was later confirmed by amino acid sequencing and modern techniques. Cleavage of Synapsin I by collaganase fragments the elongated C-terminal and leaves the globular N-terminal domain intact.
The amino acid sequencing has shown that Synapsin I has common N-terminals across both isoforms and shares the same N-terminal as Synapsin II. Synapsin I isoforms differ from Synapsin II isoforms in their C-terminal protein domains as well. Further research has been done on the interactions of Synapsin I, Synapsin II, and Synapsin III with each other to create heterodimers of the proteins in COS cells.
s based on immunocytochemistry. This phosphoprotein is as an endogenous substrate bound to the vesicular membrane. It is phosphorylated
by four known classes of protein kinase
s including those activated by cAMP
, calciuim/calmodulin, mitogen
, and cyclin
. Both isoforms have the same six phosphorylation sites:
The N-terminal globular domain contains three sites: the cAMP-dependent protein kinase-mediated phosphorylation site near the end in domain A, and two sites further in, in domain B, mediated by mitogen-activated protein kinase
(MAP kinase). The tail portion of the protein, the C-terminal end, bears three phosphorylation sites: two sites at which calcium/calmodulin dependent protein kinase II
acts, and a third site at which MAP kinase
and cyclin-dependent protein kinase
(CDK) acts. Specificity for calcium/calmodulin dependent protein kinase binding to Synapsin I is very high in comparison to other substrate proteins. Cyclic AMP-dependent protein kinase is unique in its mechanism of activation. The protein kinase is composed of two regulatory (R) subunits and two catalytic (C) subunits, creating a tetrameric holoenzyme. Cyclic AMP binds to the regulatory subunits of cAMP-dependent protein kinase and causes the dissociation of its regulatory subunits from the catalytic subunits, generating the active form of the kinase. This active form of the protein kinase catalyses the phosphorylation of Synapsin I. The phosphorylated form of Synapsin I is referred to as phosphosynapsin I.
Depolarization of the presynaptic membrane induces a calcium ion influx into the axonal nerve terminal of neurons, and increases the intracellular concentration of calcium ions. Synapsin I was shown to be phosphorylated by this calcium influx. The calcium ion, Ca2+, binds to calmodulin to form a calcium/calmodulin complex which then activates the calcium/calmodulin-dependent protein kinase, in turn triggering phosphorylation. Calcium/calmodulin-dependent phosphorylation of synapsin I causes dissociation of synapsin I from the vesicular membrane. In the nerve terminal ending, there are two pools of synaptic vesicles, the reserve pool and the ready-release pool. The reserve pool refers to the synaptic vesicles that are not ready to release neurotransmitters and the ready-release pool refers to the vesicles which are primed to release their neurotransmitters across the presynaptic cytoplasmic membrane and into the synaptic cleft. The removal of Synapsin I from synaptic vesicles is thought to mobilize synaptic vesicles from the reserve pool to the release-ready pool, thereby modulating neurotransmitter release. Since it is only present in the vesicles in the reserve pool, the non-phosphorylated form of Synapsin I is considered to be an inhibitory regulator of neurotransmission.
with NOS1AP
and SYN2
.
.
dependent protein kinase. Synapsin I was detected by radioactive P-32 incorporated into the unknown protein through phosphorylation, using at then newly developed technique: a combination of SDS gel electrophoresis and autoradiography. This groundbreaking technique allowed the advancement of the analysis of phosphorylated proteins, and introduced the identification of specific proteins. This was accomplished by the measuring the radioactivity through autoradiography of the individual protein bands phosphorylated by radioactive ATP, which is radio-labelled with P-32 at the gamma phosphate.
In 1977, at the same laboratory at Yale University, this first neuronal phosphoprotein was purified and initially characterized by Tetsufumi Ueda and Nobel Prize
winner Paul Greengard
. Originally named Protein I, it was found as an endogenous substrate for cAMP dependent protein kinase in the synaptic membrane of the rat brain and was the first collganeous protein to be described in the nervous system.
Phosphoprotein
Phosphoproteins are proteins that are physically bonded to a substance containing phosphoric acid . This category of organic molecules includes Fc receptors, Ulks, Calcineurins, K chips, and urocortins....
s that in humans are encoded by the SYN1 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. In its phosphorylated
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
form, Synapsin I may also be referred to as phosphosynaspin I. Synapsin I is the first of the proteins in the synapsin
Synapsin
The synapsins are a family of proteins that have long been implicated in the regulation of neurotransmitter release at synapses. Specifically, they are thought to be involved in regulating the number of synaptic vesicles available for release via exocytosis at any one time.Current studies suggest...
family of phosphoproteins in the synaptic vesicles present in the central and peripheral nervous systems. Synapsin Ia and Ib are close in length and almost the same in make up, however, Synapsin Ib stops short of the last segment of the C-terminal in the amino acid sequence found in Synapsin Ia.
Protein
The synapsin I protein is a member of the synapsinSynapsin
The synapsins are a family of proteins that have long been implicated in the regulation of neurotransmitter release at synapses. Specifically, they are thought to be involved in regulating the number of synaptic vesicles available for release via exocytosis at any one time.Current studies suggest...
family that are neuronal phosphoprotein
Phosphoprotein
Phosphoproteins are proteins that are physically bonded to a substance containing phosphoric acid . This category of organic molecules includes Fc receptors, Ulks, Calcineurins, K chips, and urocortins....
s which associate with the cytoplasmic surface of synaptic vesicle
Synaptic vesicle
In a neuron, synaptic vesicles store various neurotransmitters that are released at the synapse. The release is regulated by a voltage-dependent calcium channel. Vesicles are essential for propagating nerve impulses between neurons and are constantly recreated by the cell...
s. Family members are characterized by common protein domains, and they are implicated in synaptogenesis and the modulation of neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
release, suggesting a potential role in several neuropsychiatric diseases.
The phosphoprotein plays a role in regulation of axonogenesis
Axon guidance
Axon guidance is a subfield of neural development concerning the process by which neurons send out axons to reach the correct targets...
and synaptogenesis
Synaptogenesis
Synaptogenesis is the formation of synapses. Although it occurs throughout a healthy person's lifespan, an explosion of synapse formation occurs during early brain development...
. The protein serves as a substrate for several different protein kinase
Protein kinase
A protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins...
s and phosphorylation may function in the regulation of this protein in the nerve terminal.
Synapsin I is found in two isoforms of the protein, Synapsin Ia and Synapsin Ib, with Synapsin Ib being a slightly shorter version of the protein. Both Synapsin I proteins are highly basic with a pI
Isoelectric point
The isoelectric point , sometimes abbreviated to IEP, is the pH at which a particular molecule or surface carries no net electrical charge....
in the range of 10.3 and 10.2, respectively. Both isoforms are phosphorylated at identical locations within their protein sequences, specifically at the same three serine residues.
Synapsin I phosphoproteins make up approximately 6% of the total protein in synaptic vesicles. Among bovine, rat, and human it has been shown to be 95% homologous, with the central 'C' domain evolutionarily conserved. This phosphoprotein is loosely associated with the vesicular membrance and is easily dissociated by treatment with a salt, versus a detergent being required for its removal from the membrane.
Structure
The Synapsin I proteins are made up of a globular portion at the N-terminal and an elongated C-terminal domain, rendering them largely elongated proteins on the whole. Synapsin Ib has the same protein domains as Synapsin 1a, however Synapsin Ib lacks the last C-terminal segment, making it slightly shorter in its elongated domain. There are 706 amino acids that comprise Synapsin Ia and starting from the N-terminal, the same first 670 amino acids comprise Synapsin Ib.Rich in the amino acids prorine and glycine, the compositional and structural natures of this protein are somewhat similar to collagen. This aided in the early determination of its structure using collagenase, and which was later confirmed by amino acid sequencing and modern techniques. Cleavage of Synapsin I by collaganase fragments the elongated C-terminal and leaves the globular N-terminal domain intact.
The amino acid sequencing has shown that Synapsin I has common N-terminals across both isoforms and shares the same N-terminal as Synapsin II. Synapsin I isoforms differ from Synapsin II isoforms in their C-terminal protein domains as well. Further research has been done on the interactions of Synapsin I, Synapsin II, and Synapsin III with each other to create heterodimers of the proteins in COS cells.
Function
Synapsin I is present in the nerve terminal of axons, specifically in the membranes of synaptic vesicleSynaptic vesicle
In a neuron, synaptic vesicles store various neurotransmitters that are released at the synapse. The release is regulated by a voltage-dependent calcium channel. Vesicles are essential for propagating nerve impulses between neurons and are constantly recreated by the cell...
s based on immunocytochemistry. This phosphoprotein is as an endogenous substrate bound to the vesicular membrane. It is phosphorylated
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
by four known classes of protein kinase
Protein kinase
A protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins...
s including those activated by cAMP
Cyclic adenosine monophosphate
Cyclic adenosine monophosphate is a second messenger important in many biological processes...
, calciuim/calmodulin, mitogen
Mitogen
A mitogen is a chemical substance that encourages a cell to commence cell division, triggering mitosis. A mitogen is usually some form of a protein.Mitogenesis is the induction of mitosis, typically via a mitogen....
, and cyclin
Cyclin
Cyclins are a family of proteins that control the progression of cells through the cell cycle by activating cyclin-dependent kinase enzymes.- Function :...
. Both isoforms have the same six phosphorylation sites:
The N-terminal globular domain contains three sites: the cAMP-dependent protein kinase-mediated phosphorylation site near the end in domain A, and two sites further in, in domain B, mediated by mitogen-activated protein kinase
Mitogen-activated protein kinase
Mitogen-activated protein kinases are serine/threonine-specific protein kinases that respond to extracellular stimuli and regulate various cellular activities, such as gene expression, mitosis, differentiation, proliferation, and cell survival/apoptosis.-Activation:MAP kinases are activated...
(MAP kinase). The tail portion of the protein, the C-terminal end, bears three phosphorylation sites: two sites at which calcium/calmodulin dependent protein kinase II
Ca2+/calmodulin-dependent protein kinase
/calmodulin-dependent protein kinases II or CaM kinases II are serine/threonine-specific protein kinases that are regulated by the /calmodulin complex...
acts, and a third site at which MAP kinase
Mitogen-activated protein kinase
Mitogen-activated protein kinases are serine/threonine-specific protein kinases that respond to extracellular stimuli and regulate various cellular activities, such as gene expression, mitosis, differentiation, proliferation, and cell survival/apoptosis.-Activation:MAP kinases are activated...
and cyclin-dependent protein kinase
Cyclin-dependent kinase
thumb|350px|Schematic of the cell cycle. outer ring: I=[[Interphase]], M=[[Mitosis]]; inner ring: M=Mitosis; G1=[[G1 phase|Gap phase 1]]; S=[[S phase|Synthesis]]; G2=[[G2 phase|Gap phase 2]]...
(CDK) acts. Specificity for calcium/calmodulin dependent protein kinase binding to Synapsin I is very high in comparison to other substrate proteins. Cyclic AMP-dependent protein kinase is unique in its mechanism of activation. The protein kinase is composed of two regulatory (R) subunits and two catalytic (C) subunits, creating a tetrameric holoenzyme. Cyclic AMP binds to the regulatory subunits of cAMP-dependent protein kinase and causes the dissociation of its regulatory subunits from the catalytic subunits, generating the active form of the kinase. This active form of the protein kinase catalyses the phosphorylation of Synapsin I. The phosphorylated form of Synapsin I is referred to as phosphosynapsin I.
Depolarization of the presynaptic membrane induces a calcium ion influx into the axonal nerve terminal of neurons, and increases the intracellular concentration of calcium ions. Synapsin I was shown to be phosphorylated by this calcium influx. The calcium ion, Ca2+, binds to calmodulin to form a calcium/calmodulin complex which then activates the calcium/calmodulin-dependent protein kinase, in turn triggering phosphorylation. Calcium/calmodulin-dependent phosphorylation of synapsin I causes dissociation of synapsin I from the vesicular membrane. In the nerve terminal ending, there are two pools of synaptic vesicles, the reserve pool and the ready-release pool. The reserve pool refers to the synaptic vesicles that are not ready to release neurotransmitters and the ready-release pool refers to the vesicles which are primed to release their neurotransmitters across the presynaptic cytoplasmic membrane and into the synaptic cleft. The removal of Synapsin I from synaptic vesicles is thought to mobilize synaptic vesicles from the reserve pool to the release-ready pool, thereby modulating neurotransmitter release. Since it is only present in the vesicles in the reserve pool, the non-phosphorylated form of Synapsin I is considered to be an inhibitory regulator of neurotransmission.
Interactions
The synapsin I protein has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with NOS1AP
NOS1AP
Nitric oxide synthase 1 adaptor protein also known as carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase protein is a protein that in humans is encoded by the NOS1AP gene....
and SYN2
Synapsin 2
Synapsin II is the collective name for Synapsin IIa and Synapsin IIb, two nearly identical phosphoproteins in the synapsin family that in humans are encoded by the SYN2 gene...
.
Clinical significance
Mutations in the SYN1 gene may be associated with X-linked disorders with primary neuronal degeneration such as Rett syndromeRett syndrome
Rett syndrome is a neurodevelopmental disorder of the grey matter of the brain that almost exclusively affects females. The clinical features include small hands and feet and a deceleration of the rate of head growth . Repetitive hand movements, such as wringing and/or repeatedly putting hands into...
.
Discovery
The first member of the synapsin family, Synapsin I was initially observed in 1973, as a neuronal membrane protein that was phosphorylated by membrane bound cAMPCyclic adenosine monophosphate
Cyclic adenosine monophosphate is a second messenger important in many biological processes...
dependent protein kinase. Synapsin I was detected by radioactive P-32 incorporated into the unknown protein through phosphorylation, using at then newly developed technique: a combination of SDS gel electrophoresis and autoradiography. This groundbreaking technique allowed the advancement of the analysis of phosphorylated proteins, and introduced the identification of specific proteins. This was accomplished by the measuring the radioactivity through autoradiography of the individual protein bands phosphorylated by radioactive ATP, which is radio-labelled with P-32 at the gamma phosphate.
In 1977, at the same laboratory at Yale University, this first neuronal phosphoprotein was purified and initially characterized by Tetsufumi Ueda and Nobel Prize
Nobel Prize
The Nobel Prizes are annual international awards bestowed by Scandinavian committees in recognition of cultural and scientific advances. The will of the Swedish chemist Alfred Nobel, the inventor of dynamite, established the prizes in 1895...
winner Paul Greengard
Paul Greengard
Paul Greengard is an American neuroscientist best known for his work on the molecular and cellular function of neurons. In 2000, Greengard, Arvid Carlsson and Eric Kandel were awarded the Nobel Prize for Physiology or Medicine for their discoveries concerning signal transduction in the nervous...
. Originally named Protein I, it was found as an endogenous substrate for cAMP dependent protein kinase in the synaptic membrane of the rat brain and was the first collganeous protein to be described in the nervous system.