Structural and Functional Deficits in a Neuronal Calcium Sensor-1 Mutant Identified in a Case of Autistic Spectrum Disorder

Handley, Mark T.; Lian, Lu‐Yun; Haynes, Lee P.; Burgoyne, Robert D.

doi:10.1371/journal.pone.0010534

Cited by 66 publications

(93 citation statements)

References 68 publications

(107 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…IL1RAPL1 and NCS-1 are implicated in Xlinked mental retardation and autism (Handley et al, 2010;Pavlowsky et al, 2010). The autism-related missense (R102Q) mutation in NCS-1 abolishes Ca 2+ dependence, owing to a weakened conformational stability of its C-terminus that affects the cytosolic-to-membrane cycling of NCS-1 (Heidarsson et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

The guanine-exchange factor Ric8a binds the calcium sensor NCS-1 to regulate synapse number and probability of release

Romero-Pozuelo

Dason

Mansilla

et al. 2014

Journal of Cell Science

View full text Add to dashboard Cite

The conserved Ca 2+ -binding protein Frequenin (homolog of the mammalian NCS-1, neural calcium sensor) is involved in pathologies that result from abnormal synapse number and probability of neurotransmitter release per synapse. Both synaptic features are likely to be co-regulated but the intervening mechanisms remain poorly understood. We show here that Drosophila Ric8a (a homolog of mammalian synembryn, which is also known as Ric8a), a receptor-independent activator of G protein complexes, binds to Frq2 but not to the virtually identical homolog Frq1. Based on crystallographic data on Frq2 and site-directed mutagenesis on Frq1, the differential amino acids R94 and T138 account for this specificity. Human NCS-1 and Ric8a reproduce the binding and maintain the structural requirements at these key positions. Drosophila Ric8a and Gas regulate synapse number and neurotransmitter release, and both are functionally linked to Frq2. Frq2 negatively regulates Ric8a to control synapse number. However, the regulation of neurotransmitter release by Ric8a is independent of Frq2 binding. Thus, the antagonistic regulation of these two synaptic properties shares a common pathway, Frq2-Ric8a-Gas, which diverges downstream. These mechanisms expose the Frq2-Ric8a interacting surface as a potential pharmacological target for NCS-1-related diseases and provide key data towards the corresponding drug design.

show abstract

Section: Discussionmentioning

confidence: 99%

The guanine-exchange factor Ric8a binds the calcium sensor NCS-1 to regulate synapse number and probability of release

Romero-Pozuelo

Dason

Mansilla

et al. 2014

Journal of Cell Science

View full text Add to dashboard Cite

show abstract

“…NCS-1 is thought to downregulate N-type calcium channels (Handley et al 2010). For this reason, we tested the ability of the specific P/Q-type calcium channel blocker to block oscillations potentiated by 1 M NCS-1.…”

Section: Effects Of 1 M Ncs-1 On Gamma-band Oscillations In Ppn Neuronsmentioning

confidence: 99%

Modulation of gamma oscillations in the pedunculopontine nucleus by neuronal calcium sensor protein-1: relevance to schizophrenia and bipolar disorder

D’Onofrio

Kezunovic

Hyde

et al. 2015

Journal of Neurophysiology

View full text Add to dashboard Cite

D'Onofrio S, Kezunovic N, Hyde JR, Luster B, Messias E, Urbano FJ, Garcia-Rill E. Modulation of gamma oscillations in the pedunculopontine nucleus by neuronal calcium sensor protein-1: relevance to schizophrenia and bipolar disorder. J Neurophysiol 113: 709 -719, 2015. First published November 5, 2014 doi:10.1152/jn.00828.2014.-Reduced levels of gamma-band activity are present in schizophrenia and bipolar disorder patients. In the same disorders, increased neuronal calcium sensor protein-1 (NCS-1) expression was reported in a series of postmortem studies. These disorders are also characterized by sleep dysregulation, suggesting a role for the reticular activating system (RAS). The discovery of gamma-band activity in the pedunculopontine nucleus (PPN), the cholinergic arm of the RAS, revealed that such activity was mediated by high-threshold calcium channels that are regulated by NCS-1. We hypothesized that NCS-1 normally regulates gamma-band oscillations through these calcium channels and that excessive levels of NCS-1, such as would be expected with overexpression, decrease gammaband activity. We found that PPN neurons in rat brain slices manifested gamma-band oscillations that were increased by low levels of NCS-1 but suppressed by high levels of NCS-1. Our results suggest that NCS-1 overexpression may be responsible for the decrease in gamma-band activity present in at least some schizophrenia and bipolar disorder patients.

show abstract

“…NCS-1 has also been linked to serious neurodegenerative disorders including schizophrenia, bipolar disorder (BD) (32), and autism (33,34). However, the dysfunctions of NCS-1 are poorly characterized on the molecular level, and whether they involve altered functional profiles or loss of function due to formation of misfolded states is currently unknown.…”

Section: Significancementioning

confidence: 99%

Direct single-molecule observation of calcium-dependent misfolding in human neuronal calcium sensor-1

Heidarsson

Naqvi

Otazo

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Neurodegenerative disorders are strongly linked to protein misfolding, and crucial to their explication is a detailed understanding of the underlying structural rearrangements and pathways that govern the formation of misfolded states. Here we use singlemolecule optical tweezers to monitor misfolding reactions of the human neuronal calcium sensor-1, a multispecific EF-hand protein involved in neurotransmitter release and linked to severe neurological diseases. We directly observed two misfolding trajectories leading to distinct kinetically trapped misfolded conformations. Both trajectories originate from an on-pathway intermediate state and compete with native folding in a calcium-dependent manner. The relative probability of the different trajectories could be affected by modulating the relaxation rate of applied force, demonstrating an unprecedented real-time control over the free-energy landscape of a protein. Constant-force experiments in combination with hidden Markov analysis revealed the free-energy landscape of the misfolding transitions under both physiological and pathological calcium concentrations. Remarkably for a calcium sensor, we found that higher calcium concentrations increased the lifetimes of the misfolded conformations, slowing productive folding to the native state. We propose a rugged, multidimensional energy landscape for neuronal calcium sensor-1 and speculate on a direct link between protein misfolding and calcium dysregulation that could play a role in neurodegeneration.protein folding | NCS-1 | off-pathway intermediate | conformational dynamics | optical trapping

show abstract

Structural and Functional Deficits in a Neuronal Calcium Sensor-1 Mutant Identified in a Case of Autistic Spectrum Disorder

Cited by 66 publications

References 68 publications

The guanine-exchange factor Ric8a binds the calcium sensor NCS-1 to regulate synapse number and probability of release

The guanine-exchange factor Ric8a binds the calcium sensor NCS-1 to regulate synapse number and probability of release

Modulation of gamma oscillations in the pedunculopontine nucleus by neuronal calcium sensor protein-1: relevance to schizophrenia and bipolar disorder

Direct single-molecule observation of calcium-dependent misfolding in human neuronal calcium sensor-1

Contact Info

Product

Resources

About