Impact of continuous positive airway pressure on cognitive functions in adult patients with obstructive sleep apnea: A systematic review and meta-analysis.

Background: Obstructive sleep apnea (OSA) is associated with the impairment of a range of cognitive functions. Whether treatment with continuous positive airway pressure (CPAP) improves these cognitive functions is still a matter of debate.

Methods: We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) that included OSA patients (apnea hypopnea index, AHI >10/h), naive to CPAP treatment, with a cognitive assessment before and after CPAP initiation.

CK2-regulated schwannomin-interacting protein IQCJ-SCHIP-1 association with AnkG contributes to the maintenance of the axon initial segment.

The axon initial segment (AIS) plays a central role in electrogenesis and in the maintenance of neuronal polarity. Its molecular organization is dependent on the scaffolding protein ankyrin (Ank) G and is regulated by kinases. For example, the phosphorylation of voltage-gated sodium channels by the protein kinase CK2 regulates their interaction with AnkG and, consequently, their accumulation at the AIS.

CK2 accumulation at the axon initial segment depends on sodium channel Nav1.

Accumulation of voltage-gated sodium channel Nav1 at the axon initial segment (AIS), results from a direct interaction with ankyrin G. This interaction is regulated in vitro by the protein kinase CK2, which is also highly enriched at the AIS. Here, using phosphospecific antibodies and inhibition/depletion approaches, we showed that Nav1 channels are phosphorylated in vivo in their ankyrin-binding motif.

Tetrodotoxin-resistant voltage-gated sodium channel Nav 1.8 constitutively interacts with ankyrin G.

The tetrodotoxin-resistant (TTX-R) voltage-gated sodium channel Nav 1.8 is predominantly expressed in peripheral afferent neurons, but in case of neuronal injury an ectopic and detrimental expression of Nav 1.8 occurs in neurons of the CNS.

No Pasaran! Role of the axon initial segment in the regulation of protein transport and the maintenance of axonal identity.

The transmission of information in the brain depends on the highly polarized architecture of neurons. A number of cellular transport processes support this organization, including active targeting of proteins and passive corralling between compartments. The axon initial segment (AIS), which separates the somatodendritic and axonal compartments, has a key role in neuronal physiology, as both the initiation site of action potentials and the gatekeeper of the axonal arborization.

Motor endplate disease affects neuromuscular junction maturation.

Postnatal formation of the neuromuscular synapse requires complex interactions among nerve terminal, muscle fibres and terminal Schwann cells. In motor endplate disease (med) mice, neuromuscular transmission is severely impaired without alteration of axonal conduction and a lethal paralytic phenotype occurs during the postnatal period. The med phenotype appears at a crucial stage of the neuromuscular junction development, corresponding to the increase in terminal Schwann cell number, the elimination of the multiple innervations and the pre- and postsynaptic maturation.

End-binding proteins EB3 and EB1 link microtubules to ankyrin G in the axon initial segment.

The axon initial segment (AIS) plays a key role in maintaining the molecular and functional polarity of the neuron. The relationship between the AIS architecture and the microtubules (MTs) supporting axonal transport is unknown. Here we provide evidence that the MT plus-end-binding (EB) proteins EB1 and EB3 have a role in the AIS in addition to their MT plus-end tracking protein behavior in other neuronal compartments.

Cdk-mediated phosphorylation of the Kvβ2 auxiliary subunit regulates Kv1 channel axonal targeting.

Kv1 channels are concentrated at specific sites in the axonal membrane, where they regulate neuronal excitability. Establishing these distributions requires regulated dissociation of Kv1 channels from the neuronal trafficking machinery and their subsequent insertion into the axonal membrane. We find that the auxiliary Kvβ2 subunit of Kv1 channels purified from brain is phosphorylated on serine residues 9 and 31, and that cyclin-dependent kinase (Cdk)-mediated phosphorylation at these sites negatively regulates the interaction of Kvβ2 with the microtubule plus end-tracking protein EB1.

Ankyrin G restricts ion channel diffusion at the axonal initial segment before the establishment of the diffusion barrier.

In mammalian neurons, the precise accumulation of sodium channels at the axonal initial segment (AIS) ensures action potential initiation. This accumulation precedes the immobilization of membrane proteins and lipids by a diffusion barrier at the AIS. Using single-particle tracking, we measured the mobility of a chimeric ion channel bearing the ankyrin-binding motif of the Nav1.

Determinants of voltage-gated sodium channel clustering in neurons.

In mammalian neurons, the generation and propagation of the action potential result from the presence of dense clusters of voltage-gated sodium channels (Nav) at the axonal initial segment (AIS) and nodes of Ranvier. In these two structures, the assembly of specific supra-molecular complexes composed of numerous partners, such as cytoskeletal scaffold proteins and signaling proteins ensures the high concentration of Nav channels. Understanding how neurons regulate the expression and discrete localization of Nav channels is critical to understanding the diversity of normal neuronal function as well as neuronal dysfunction caused by defects in these processes.

Voltage-gated sodium channel organization in neurons: protein interactions and trafficking pathways.

In neurons, voltage-gated sodium (Nav) channels underlie the generation and propagation of the action potential. The proper targeting and concentration of Nav channels at the axon initial segment (AIS) and at the nodes of Ranvier are therefore vital for neuronal function. In AIS and nodes, Nav channels are part of specific supra-molecular complexes that include accessory proteins, adhesion proteins and cytoskeletal adaptors.

The somatostatin 2A receptor is enriched in migrating neurons during rat and human brain development and stimulates migration and axonal outgrowth.

The neuropeptide somatostatin has been suggested to play an important role during neuronal development in addition to its established modulatory impact on neuroendocrine, motor and cognitive functions in adults. Although six somatostatin G protein-coupled receptors have been discovered, little is known about their distribution and function in the developing mammalian brain. In this study, we have first characterized the developmental expression of the somatostatin receptor sst2A, the subtype found most prominently in the adult rat and human nervous system.

Protein kinase CK2 contributes to the organization of sodium channels in axonal membranes by regulating their interactions with ankyrin G.

In neurons, generation and propagation of action potentials requires the precise accumulation of sodium channels at the axonal initial segment (AIS) and in the nodes of Ranvier through ankyrin G scaffolding. We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126).

Schwannomin-interacting protein-1 isoform IQCJ-SCHIP-1 is a late component of nodes of Ranvier and axon initial segments.

Axon initial segments (AISs) and nodes of Ranvier (NRs) are essential regions for saltatory conduction of the action potential along the axon. These two domains are enriched in similar multimolecular complexes, which include voltage-gated sodium channels (Na(v)), NF186 (neurofascin 186), NrCAM (neuron glia-related cell adhesion molecule), and cytoskeleton linkers ankyrin G (AnkG) and betaIV-spectrin. Identification of novel members of these complexes is critical to better understand their formation, function, and maintenance.

Targeting of proteins of the striatin family to dendritic spines: role of the coiled-coil domain.

Striatin, SG2NA and zinedin, the three mammalian members of the striatin family are multimodular WD-repeat, calmodulin and calveolin-binding proteins. These scaffolding proteins, involved in both signaling and trafficking, are highly expressed in neurons. Using ultrastructural immunolabeling, we showed that, in Purkinje cells and hippocampal neurons, SG2NA is confined to the somatodendritic compartment with the highest density in dendritic spines.

Endocytotic elimination and domain-selective tethering constitute a potential mechanism of protein segregation at the axonal initial segment.

The axonal initial segment is a unique subdomain of the neuron that maintains cellular polarization and contributes to electrogenesis. To obtain new insights into the mechanisms that determine protein segregation in this subdomain, we analyzed the trafficking of a reporter protein containing the cytoplasmic II-III linker sequence involved in sodium channel targeting and clustering. Here, we show that this reporter protein is preferentially inserted in the somatodendritic domain and is trapped at the axonal initial segment by tethering to the cytoskeleton, before its insertion in the axonal tips.

Dynamic compartmentalization of the voltage-gated sodium channels in axons.

One of the major physiological roles of the neuronal voltage-gated sodium channel is to generate action potentials at the axon hillock/initial segment and to ensure propagation along myelinated or unmyelinated fibers to nerve terminal. These processes require a precise distribution of sodium channels accumulated at high density in discrete subdomains of the nerve membrane. In neurons, information relevant to ion channel trafficking and compartmentalization into sub-domains of the plasma membrane is far from being elucidated.

A targeting motif involved in sodium channel clustering at the axonal initial segment.

The sorting of sodium channels to axons and the formation of clusters are of primary importance for neuronal electrogenesis. Here, we showed that the cytoplasmic loop connecting domains II and III of the Nav1 subunit contains a determinant conferring compartmentalization in the axonal initial segment of rat hippocampal neurons. Expression of a soluble Nav1.

Identification of an axonal determinant in the C-terminus of the sodium channel Na(v)1.2.

To obtain a better understanding of how hippocampal neurons selectively target proteins to axons, we assessed whether any of the large cytoplasmic regions of neuronal sodium channel Na(v)1.2 contain sufficient information for axonal compartmentalization. We show that addition of the cytoplasmic C-terminal region of Na(v)1.

Na(+) channel regulation by calmodulin kinase II in rat cerebellar granule cells.

The effects of specific CaM kinase II inhibitors were investigated on Na(+) channels from rat cerebellar granule cells. A maximal effect of KN-62 was observed at 20 microM and consisted of an 80% reduction of the peak Na(+) current after only a 10-min application. A hyperpolarizing shift of 8 mV in the steady-state inactivation was also observed.

Synaptotagmin I and IV define distinct populations of neuronal transport vesicles.

Mammalian synaptotagmins constitute a multigene family of at least 11 membrane proteins. We have characterized synaptotagmin IV using antibodies directed against the C2A domain of the protein. Antibodies reacted specifically with a protein band that migrated as a 41-44 kDa doublet.