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Enzymatic proteins

1. Tyrosine Hydroxylase (TH)

Molecular structure

Tyrosine hydroxylase is a tetrameric enzyme, with each subunit weighing approximately 60 kDa, that requires tetrahydrobiopterin (BH4) as a cofactor. Each subunit consists of a catalytic domain, which binds tyrosine and BH4, and a regulatory N-terminal domain containing phosphorylation sites. Tyrosine hydroxylase serves as the rate-limiting enzyme in the synthesis of catecholamines, including dopamine, norepinephrine, and epinephrine.

Origin/biogenesis

TH is primarily expressed in dopaminergic neurons of the substantia nigra and ventral tegmental area, noradrenergic neurons of the locus coeruleus, and in the adrenal medulla. Its transcription is regulated by neuronal activity, growth factors such as GDNF, and stress hormones. Post-translational regulation, particularly phosphorylation, enhances its catalytic activity.

Disease associations

In Parkinson’s disease, degeneration of tyrosine hydroxylase (TH)-positive neurons reduces TH levels in the nigrostriatal system. Dopa-responsive dystonia (Segawa disease) results from mutations in TH or defects in BH4 metabolism, causing decreased dopamine synthesis. Research has also linked altered TH expression to catecholaminergic dysregulation in conditions such as autism and ADHD. Exposure to neurotoxins, including MPTP and methamphetamine, can further decrease TH expression and enzymatic activity.

2. Glutamate Decarboxylase (GAD65 and GAD67)

Molecular structure

Glutamate decarboxylase (GAD) enzymes are pyridoxal phosphate (PLP)–dependent and exist in two major isoforms. GAD65, encoded by the GAD2 gene, is membrane-associated and concentrated in nerve terminals, whereas GAD67, encoded by the GAD1 gene, is cytosolic and accounts for the majority of baseline GABA synthesis. Both isoforms function as dimers, with a total molecular weight of approximately 140 kDa.

Origin/biogenesis

Glutamate decarboxylase is expressed in GABAergic neurons throughout the cortex, hippocampus, basal ganglia, and cerebellum. Its activity is regulated by neuronal activity and the availability of pyridoxal phosphate (vitamin B6). GAD65 undergoes palmitoylation, which targets it to synaptic vesicles for efficient GABA release.

Disease associations

Reduced expression of GAD67 is associated with impaired GABA synthesis and increased neuronal excitability in epilepsy. In stiff-person syndrome, autoimmune antibodies target GAD65, while GAD65 also serves as a major autoantigen in type 1 diabetes, affecting peripheral tissues rather than the CNS. Decreased GAD67 levels in parvalbumin-expressing interneurons have been observed in schizophrenia. Additionally, vitamin B6 deficiency in infants impairs GAD activity, leading to seizures.

3. Acetylcholinesterase (AChE)

Molecular structure

Acetylcholinesterase is a serine hydrolase located in synaptic clefts and at neuromuscular junctions. It exists in two main forms: tetramers anchored to membranes via PRiMA or collagen-like Q-subunits, and soluble monomers present in cerebrospinal fluid. Its catalytic site contains the characteristic Ser–His–Glu triad typical of esterases.

Origin/biogenesis

Acetylcholinesterase is synthesized in cholinergic neurons, including those of the basal forebrain and brainstem nuclei. The glycoprotein undergoes processing in the endoplasmic reticulum and Golgi apparatus before being trafficked to synapses. Its expression is tightly regulated to correspond with the density of cholinergic synapses.

Disease associations

In Alzheimer’s disease, acetylcholinesterase (AChE) levels are reduced in the cortex and hippocampus due to loss of cholinergic neurons, forming the basis for treatment with AChE inhibitors such as donepezil and rivastigmine. Organophosphate poisoning causes irreversible inhibition of AChE, leading to a cholinergic crisis. In myasthenia gravis, AChE inhibitors are used therapeutically to prolong the action of acetylcholine at neuromuscular junctions. Congenital AChE deficiency can result in prolonged apnea after succinylcholine administration.

4. Mitochondrial enzymes (representative examples)

A. Pyruvate Dehydrogenase Complex (PDH) Molecular structure Multienzyme complex with E1, E2, and E3 components. Requires thiamine, lipoic acid, FAD, NAD⁺, and CoA. Origin Nuclear-encoded, imported into mitochondria via TOM/TIM complexes. Disease associations PDH deficiency: lactic acidosis, neurodevelopmental delay. Mitochondrial disorders: impaired oxidative metabolism, energy failure in the CNS.

B. Cytochrome c Oxidase (Complex IV) Molecular structure Terminal enzyme of the electron transport chain. Contains heme a, heme a3, and copper centers (CuA, CuB). Origin Subunits are encoded by both mitochondrial DNA (mtDNA) and nuclear DNA. Disease associations Leigh syndrome, mitochondrial encephalomyopathies from Complex IV deficiency.

C. ATP Synthase Molecular structure F1 catalytic head + Fo proton channel. The rotational mechanism converts the proton gradient into ATP. Origin Assembled from nuclear and mtDNA-encoded subunits. Disease associations mtDNA mutations → energy failure, neuropathy, ataxia, encephalopathy.

D. Mitochondrial superoxide dismutase (MnSOD, SOD2) Molecular structure Homotetrameric enzyme in the mitochondrial matrix. Requires manganese. Disease associations Oxidative stress–related neurodegeneration (ALS, Parkinson’s). SOD2 deficiency is lethal without antioxidant rescue

Receptor proteins (Neurotransmitter receptors)

1. NMDA Receptors (N-Methyl-D-Aspartate)

Molecular structure

The NMDA receptor is an ionotropic glutamate receptor that functions as a tetrameric complex, typically composed of two GluN1 and two GluN2 subunits. Each subunit contains an extracellular ligand-binding domain, a transmembrane domain that forms a cation-permeable channel for Na⁺, K⁺, and Ca²⁺, and an intracellular C-terminal domain involved in signaling and scaffolding interactions. Receptor activation requires the co-agonists glutamate and glycine, and at resting membrane potential, the channel is blocked by Mg²⁺ in a voltage-dependent manner.

Origin/biogenesis

NMDA receptors are synthesized in the neuronal soma and trafficked through the endoplasmic reticulum and Golgi apparatus to dendritic spines. At synapses, they are anchored in the postsynaptic density through interactions with scaffolding proteins such as PSD-95. The subunit composition of NMDA receptors is dynamically regulated during development and during activity-dependent synaptic plasticity.

Disease associations

Mutations in GRIN genes encoding NMDA receptor subunits are associated with neurodevelopmental disorders, including intellectual disability and epilepsy. In stroke and other excitotoxic conditions, excessive NMDA receptor activation leads to calcium overload and subsequent neuronal death. NMDA receptor hypofunction has also been implicated in the pathophysiology of schizophrenia, particularly in relation to cognitive impairment and negative symptoms.

2. AMPA Receptors (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)

Molecular structure

AMPA receptors are tetrameric glutamate receptors composed of GluA1–4 subunits and are responsible for fast excitatory synaptic transmission in the central nervous system. They mediate rapid depolarization through permeability to Na⁺ and, in some subunit configurations, Ca²⁺, with calcium permeability determined largely by RNA editing of the GluA2 subunit. The cytoplasmic C-terminal domains interact with scaffolding and regulatory proteins such as GRIP and PICK1, which control receptor trafficking and synaptic localization.

Origin/biogenesis

AMPA receptor subunits are synthesized in the neuronal soma and trafficked in vesicles to synaptic membranes. During synaptic plasticity, including long-term potentiation and long-term depression, local translation in dendrites contributes to activity-dependent changes in receptor availability. The insertion and removal of AMPA receptors at synapses are tightly regulated by neuronal activity.

Disease associations

In patients with epilepsy, altered trafficking and regulation of AMPA receptors contribute to neuronal hyperexcitability. In autism spectrum disorder, synaptic dysfunction has been linked to mutations in GluA subunits and associated regulatory proteins. In neurodegenerative conditions such as Alzheimer’s disease, excessive glutamatergic signaling and AMPA receptor–mediated excitotoxicity contribute to neuronal injury and synaptic loss.

3. GABA Receptors

i. GABA-A (Ionotropic)

The GABA-A receptor is a pentameric chloride channel composed of various combinations of α, β, γ, δ, or ε subunits. It mediates fast inhibitory neurotransmission in the central nervous system, and its specific subunit composition determines its pharmacological properties, including sensitivity to benzodiazepines.

ii. GABA-B (Metabotropic)

The GABA-B receptor is a G-protein–coupled receptor that functions as an obligate heterodimer composed of GABA-B1 and GABA-B2 subunits. Upon activation, it couples to Gi/o proteins, leading to decreased cyclic AMP levels, opening of potassium channels, and inhibition of voltage-gated calcium channels, thereby producing slow inhibitory synaptic effects.

Origin/biogenesis

GABA receptors are expressed in inhibitory interneurons as well as in their postsynaptic target neurons. GABA-A receptor subunits are assembled in the endoplasmic reticulum and subsequently trafficked to synapses, whereas GABAB-B receptors are processed and transported via the Golgi apparatus. Synaptic localization and stabilization are regulated by scaffolding and auxiliary proteins, including gephyrin for GABA-A receptors and KCTD proteins for GABA-B receptors.

Disease associations

Mutations in GABA-A receptor subunits impair inhibitory neurotransmission and increase neuronal excitability, which is one of the primary mechanisms in epileptic seizures. Disorders such as anxiety and insomnia are linked to altered GABAergic signaling and are commonly treated pharmacologically with benzodiazepines, which act on GABA-A receptors. In conditions characterized by spasticity and specific pain syndromes, modulation of GABA-B receptors is therapeutically exploited, most notably with baclofen.

4. Dopamine Receptors (D1–D5)

Molecular structure

Dopamine receptors belong to the G-protein–coupled receptor family and are characterized by seven transmembrane helices, an extracellular N-terminus, and an intracellular C-terminus. They are divided into two major classes based on signaling properties: D1-like receptors (D1 and D5), which couple to Gs proteins and increase intracellular cAMP levels, and D2-like receptors (D2, D3, and D4), which couple to Gi proteins and decrease intracellular cAMP levels.

Origin/biogenesis

Dopamine receptors are expressed in striatal, cortical, and limbic neurons. They are trafficked from the endoplasmic reticulum to the plasma membrane, and phosphorylation and interactions with β-arrestins regulate their surface localization. Receptor density and signaling sensitivity are dynamically modulated by dopamine availability.

Disease associations

In Parkinson’s disease, degeneration of nigrostriatal dopaminergic neurons leads to disrupted D1- and D2-receptor signaling within basal ganglia circuits. In schizophrenia, hyperactive D2 receptor signaling in the mesolimbic pathway is implicated in positive symptoms, while reduced dopaminergic signaling in the prefrontal cortex, particularly involving D1 receptors, contributes to cognitive and negative symptoms. In drug addiction, repeated exposure to addictive substances induces adaptive changes in dopamine receptor expression and signaling, reinforcing maladaptive reward-related behaviors.

5. Serotonin Receptors (5-HT Family)

Molecular structure

Serotonin (5-HT) receptors comprise multiple molecular families. The 5-HT1, 5-HT2, and 5-HT4–7 receptors are G-protein–coupled receptors, whereas the 5-HT3 receptor is a pentameric ligand-gated cation channel. The GPCR subtypes couple to different intracellular signaling pathways, including Gs, Gi, and Gq, thereby modulating cyclic AMP levels, phospholipase C activity, and potassium and calcium channel function.

Origin/biogenesis

Serotonin receptors are synthesized in serotonergic neurons of the raphe nuclei or expressed in their target neurons and are trafficked to somatic and dendritic membranes. Their surface expression is dynamically regulated through phosphorylation-dependent receptor internalization, recycling, and endocytosis.

Disease associations

Serotonin receptors are implicated in several neuropsychiatric and neurological disorders. In depression and anxiety, serotonergic signaling is a primary therapeutic target of selective serotonin reuptake inhibitors, with particular involvement of 5-HT1A and 5-HT2 receptors. In schizophrenia, antagonism of 5-HT2A receptors is a key mechanism of action of atypical antipsychotic drugs. In migraine, agonists of 5-HT1B and 5-HT1D receptors, known as triptans, are used to abort acute attacks by modulating cranial vascular and trigeminovascular signaling.

Ion channel proteins

1. Voltage-gated Sodium Channels (Na⁺)

Molecular structure

Voltage-gated sodium channels are composed of a large α-subunit of approximately 260 kDa that contains four homologous domains, each consisting of six transmembrane helices. One or more β-subunits associate with the α-subunit to modulate channel kinetics, voltage dependence, and subcellular localization. These channels open rapidly in response to membrane depolarization, allowing sodium influx that initiates the neuronal action potential.

Origin/biogenesis

Voltage-gated sodium channels are synthesized in the neuronal soma and subsequently trafficked to the axon initial segment and the nodes of Ranvier. Their high local channel density at these specialized membrane domains is regulated by ankyrin G and associated scaffolding proteins.

Disease associations

Mutations in voltage-gated sodium channel genes are associated with several neurological and systemic disorders. In epilepsy, pathogenic variants in SCN1A and SCN2A cause gain- or loss-of-function effects that disrupt neuronal excitability. Mutations in Nav1.7–Nav1.9 channels are linked to periodic paralysis and a range of inherited pain syndromes. Certain sodium channel isoforms are expressed in both the central nervous system and the heart, and their dysfunction can contribute to cardiac arrhythmias.

2. Voltage-gated Potassium Channels (K⁺)

Molecular structure

Voltage-gated potassium channels are composed of four α-subunits arranged as a tetramer, with each subunit containing six transmembrane segments. These channels are essential for controlling action potential repolarization and regulating overall neuronal excitability.

Origin/biogenesis

Voltage-gated potassium channels are expressed throughout neurons, including the soma, dendrites, and axons. Accessory β-subunits and other associated proteins guide their trafficking and precise subcellular localization.

Disease associations

Mutations in voltage-gated potassium channel genes are linked to a range of neurological disorders. Epilepsy and ataxia can result from pathogenic variants in KCNA1 and KCNQ2/3, while channelopathies affecting both the central and peripheral nervous systems may cause myokymia and periodic paralysis.

3. Voltage-gated Calcium Channels (Ca²⁺)

Molecular structure

Voltage-gated calcium channels are multi-subunit complexes composed of a pore-forming α1 subunit along with auxiliary α2δ, β, and γ subunits. These channels mediate calcium influx in response to membrane depolarization, triggering neurotransmitter release and initiating calcium-dependent gene transcription.

Origin/biogenesis

Voltage-gated calcium channels are synthesized in the neuronal soma and targeted to presynaptic terminals. Their subunit composition determines channel kinetics, voltage dependence, and pharmacological properties, giving rise to functionally distinct types such as L-, N-, and P/Q-type channels.

Disease associations

Mutations in voltage-gated calcium channel genes are associated with various neurological disorders. CACNA1A mutations affecting P/Q-type channels can cause migraine and ataxia, while CACNA1H mutations are linked to epilepsy. Dysregulated calcium influx through these channels can also contribute to neurodegeneration via excitotoxic mechanisms.

Transport protein

1. Synaptophysin

Molecular structure

Synaptophysin is an integral membrane glycoprotein of synaptic vesicles with a molecular weight of approximately 38 kDa. It contains four transmembrane domains, with both the N- and C-termini facing the cytoplasm. Synaptophysin forms tetramers and interacts with components of the vesicle fusion machinery, contributing to synaptic vesicle organization and neurotransmitter release.

Origin/biogenesis

Synaptophysin is synthesized in the neuronal soma, inserted into endoplasmic reticulum membranes, processed through the Golgi apparatus, and then transported to presynaptic terminals. It is specifically localized to synaptic vesicles, where it serves as a reliable marker of presynaptic sites.

Disease associations

In neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s disease, synaptophysin immunoreactivity is reduced, reflecting synaptic loss. In schizophrenia and other cognitive disorders, altered presynaptic density is associated with decreased synaptophysin expression. In epilepsy, particularly in hippocampal sclerosis, reduced synaptophysin levels indicate loss or reorganization of presynaptic terminals.

2. Vesicular Transporters:

A. VMAT (Vesicular Monoamine Transporter)

Molecular structure

Vesicular monoamine transporters are integral membrane proteins of synaptic vesicles with 12 transmembrane domains. They use the vesicular proton gradient to transport monoamines, including dopamine, norepinephrine, and serotonin, from the cytosol into synaptic vesicles for regulated neurotransmitter release.

Origin/biogenesis

Vesicular monoamine transporters are synthesized in the neuronal soma and trafficked through the endoplasmic reticulum and Golgi apparatus to presynaptic vesicles. Their expression is regulated by neuronal activity and the availability of monoamine neurotransmitters.

Disease associations

Dysfunction of vesicular monoamine transporters, particularly VMAT2, is implicated in several neurological and psychiatric conditions. In Parkinson’s disease, impaired loading of dopamine into synaptic vesicles contributes to cytosolic dopamine toxicity and neurodegeneration. In depression and other psychiatric disorders, altered VMAT2 function affects monoamine storage and release. Pharmacological inhibition of VMAT2 with tetrabenazine is used therapeutically to reduce chorea in Huntington’s disease.

B. VGLUT (Vesicular Glutamate Transporter)

Vesicular glutamate transporters are responsible for transporting glutamate into synaptic vesicles for excitatory neurotransmission. Three main isoforms, VGLUT1, VGLUT2, and VGLUT3, are expressed in a tissue- and circuit-specific manner, with prominent distribution in cortical and hippocampal neurons as well as in various subcortical regions.

Disease associations

Altered expression or dysregulation of vesicular glutamate transporters has been implicated in several neurological and psychiatric conditions, including epilepsy, neurodevelopmental disorders, and mood disorders, reflecting disturbed excitatory neurotransmission.

C. VGAT (Vesicular GABA Transporter, also VIAAT)

The vesicular GABA transporter (VGAT), also known as VIAAT, transports GABA and glycine into synaptic vesicles and is essential for effective inhibitory neurotransmission in the central nervous system.

Disease associations

Mutations affecting the vesicular GABA transporter lead to impaired inhibitory neurotransmission, resulting in neuronal hyperexcitability and epilepsy. Reduced VGAT expression has also been observed in experimental models of schizophrenia and autism, supporting a role for disrupted inhibitory synaptic transmission in these disorders.

3. Glucose Transporters (GLUT1, GLUT3):

A. GLUT1

Molecular structure

GLUT1 is a facilitative glucose transporter with 12 transmembrane domains, primarily expressed in endothelial cells of the blood–brain barrier. It mediates basal glucose transport from the bloodstream into the brain parenchyma, ensuring a steady energy supply for neuronal function.

Origin/biogenesis

GLUT1 is synthesized in blood–brain barrier endothelial cells and inserted into the plasma membrane. Proper folding and stability of the transporter critically depend on glycosylation.

Disease associations

GLUT1 deficiency syndrome is caused by mutations in the SLC2A1 gene, leading to impaired glucose transport into the brain. This results in developmental delay, seizures, and movement disorders due to energy deficiency in neurons.

B. GLUT3

GLUT3 is a high-affinity glucose transporter predominantly expressed in neurons. It is localized on neuronal somata and dendrites to support energy-demanding processes such as synaptic activity and action potential generation.

Disease associations

Reduced GLUT3 expression has been observed in Alzheimer’s disease, contributing to neuronal energy deficits. Impaired GLUT3 function is also associated with increased sensitivity to hypoglycemia and may contribute to certain neurodevelopmental disorders.

4. Axonal Transport Motors:

A. Kinesin

Molecular structure

Kinesin is a motor protein composed of three main domains: a head domain with ATPase activity, a stalk, and a tail. It transports cargo along microtubules in the anterograde direction, from the neuronal soma toward axon terminals, using energy derived from ATP hydrolysis.

Origin/biogenesis

Kinesin is synthesized in the neuronal soma and associates with specific cargo, such as vesicles, organelles, and mitochondria, through adaptor proteins. Cargo specificity is primarily determined by kinesin light chains, which recognize distinct cargo signals.

Disease associations

Mutations in kinesin family proteins are linked to several neurological disorders. In Charcot–Marie–Tooth disease type 2 A(CMT2A), KIF1B mutations impair axonal transport. Defective kinesin-mediated transport also contributes to axonal degeneration in amyotrophic lateral sclerosis and other motor neuron diseases. More broadly, impaired transport of mitochondria and synaptic vesicles is implicated in neurodegenerative conditions such as Alzheimer’s and Huntington’s disease.

B. Dynein

Molecular structure

Cytoplasmic dynein is a multi-subunit motor protein complex composed of a heavy chain with ATPase activity, along with intermediate, light intermediate, and light chains. It mediates retrograde transport of cargo along microtubules, moving materials from axon terminals back to the neuronal soma.

Disease associations

Mutations in dynein and its cofactor dynactin are associated with spinal muscular atrophy and amyotrophic lateral sclerosis, where disrupted retrograde transport contributes to motor neuron degeneration. Impaired dynein-mediated trafficking also leads to the accumulation of misfolded proteins, promoting neurodegeneration. In Charcot–Marie–Tooth disease type 2O, mutations in the DYNC1H1 gene compromise axonal integrity and function.

Signalin proteins

1. G-Proteins (Guanine Nucleotide-binding Proteins)

Molecular structure

Heterotrimeric G proteins are composed of three subunits: α, β, and γ. The α subunit binds GDP and GTP and possesses intrinsic GTPase activity, thereby regulating signaling duration. The dimer functions as a signaling unit that modulates ion channels and various effector proteins. G-protein activates G protein–coupled receptors, which promote GDP–GTP exchange on the α subunit upon ligand binding.

Origin/biogenesis

Heterotrimeric G proteins are synthesized in the neuronal soma and undergo lipid modifications such as myristoylation and palmitoylation, which are essential for membrane anchoring. They localize primarily to the plasma membrane but are also found on intracellular membranes. Their activation follows a cyclical process in which the GDP-bound inactive form is converted to a GTP-bound active state upon receptor stimulation, followed by intrinsic GTP hydrolysis that returns the α subunit to the inactive GDP-bound form.

Disease associations

Mutations in genes encoding G-protein subunits, such as GNAO1, GNAS, and GNB1, are associated with neurodevelopmental disorders characterized by epilepsy, movement disorders, and intellectual disability. Altered G-protein signaling has also been implicated in psychiatric conditions, including depression and schizophrenia. In neurodegenerative diseases, disruption of GPCR–G-protein signaling pathways contributes to synaptic dysfunction and cognitive decline.

2. Kinases:

A. CaMKII (Calcium/Calmodulin-dependent Protein Kinase II)

Molecular structure

CaMKII is a calcium/calmodulin-dependent protein kinase that forms a multimeric holoenzyme composed of approximately 12–14 subunits. Each subunit contains a catalytic domain, a regulatory domain that binds the Ca²⁺/calmodulin complex, and an association domain responsible for holoenzyme assembly. Autophosphorylation of CaMKII enables the kinase to maintain sustained activity even after intracellular calcium levels have declined, providing a molecular mechanism for activity-dependent signal integration.

Origin/biogenesis

CaMKII is synthesized in the neuronal soma and dendrites, with additional local translation occurring within dendritic spines. It is targeted to the postsynaptic density through interactions with NMDA receptor complexes and associated scaffolding proteins, thereby coupling calcium influx to synaptic signaling.

Disease associations

Impaired CaMKII activity is associated with cognitive disorders, including defective long-term potentiation and disturbances in learning and memory. In addition, pathogenic mutations affecting CaMKII have been linked to neurodevelopmental disorders, including intellectual disability and epilepsy.

B. MAPK (Mitogen-Activated Protein Kinases)

Molecular structure

Mitogen-activated protein kinases (MAPKs) comprise a family of serine/threonine kinases that includes ERK, JNK, and p38. These kinases are activated through a conserved three-tiered signaling cascade that sequentially activates MAP kinase kinase kinases (MAPKKKs), MAP kinase kinases (MAPKKs), and, finally, MAPKs. Once activated, MAPKs phosphorylate specific substrates to regulate gene transcription, cytoskeletal dynamics, and apoptotic pathways.

Origin/biogenesis

MAPKs are synthesized in the cytoplasm and, upon activation, translocate to the nucleus where they influence gene expression. Their activation is triggered by a wide range of signals, including growth factors, neurotransmitters, and cellular stress stimuli.

Disease associations

Dysregulated MAPK signaling is implicated in multiple neurological and psychiatric conditions. Overactivation of MAPK pathways contributes to neuronal dysfunction and cell death in neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. Mutations affecting components of the MAPK pathway underlie neurodevelopmental disorders known as RASopathies, which are frequently associated with cognitive deficits. Altered ERK signaling has also been observed in mood disorders, including depression and bipolar disorder.

3. Phosphatases

Molecular structure

Phosphatases are enzymes that remove phosphate groups from proteins, thereby counteracting the actions of kinases and providing tight control over cellular signaling. Major classes include protein phosphatase 1 (PP1), a serine/threonine phosphatase; protein phosphatase 2A (PP2A), which functions as a heterotrimeric complex; and protein tyrosine phosphatases (PTPs), which regulate signaling downstream of receptors and within intracellular pathways.

Origin/biogenesis

Phosphatases are synthesized in the neuronal soma and are subsequently localized to specific compartments, including synapses, the cytoplasm, or the nucleus. Their enzymatic activity is tightly regulated by subunit composition, phosphorylation, and interactions with endogenous inhibitor proteins.

Disease associations

Dysregulation of phosphatases is implicated in multiple neurological disorders. In Alzheimer’s disease, impaired PP2A activity leads to tau hyperphosphorylation and formation of neurofibrillary tangles. Altered phosphatase function in epilepsy contributes to neuronal hyperexcitability. In neurodevelopmental disorders, improper dephosphorylation disrupts synaptic plasticity, affecting learning and cognitive function.

4. Calmodulin (CaM)

Molecular structure

Calmodulin (CaM) is a small calcium-binding protein of approximately 17 kDa. It contains four EF-hand motifs that bind Ca²⁺, inducing a conformational change that enables calmodulin to activate a variety of target proteins, including CaMKII and phosphodiesterases.

Origin/biogenesis

Calmodulin is synthesized in the neuronal soma and is ubiquitously distributed throughout the cytoplasm and dendrites. In response to elevations in intracellular Ca²⁺, it rapidly translocates to and binds target proteins to mediate calcium-dependent signaling.

Disease associations

Mutations in CALM genes encoding calmodulin are linked to neurodevelopmental disorders due to impaired calcium signaling. In neurodegenerative diseases, defective calmodulin regulation contributes to excitotoxic neuronal injury. Certain CALM mutations also produce combined cardiac and neurological phenotypes, reflecting the protein’s critical roles in both tissues.

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