Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.1.4.3 (
phospholipase C
)
18,461
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Sporadic amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects particularly motoneurons. Several pieces of evidence suggested the involvement of autoimmune mechanisms mediated by antibodies in ALS. However, the significance of those antibodies in the disease and the underlying mechanisms are unknown. Here we showed that IgG purified from a group of sporadic ALS patients, but not familial ALS patients, specifically interact with the presynaptic membrane of motoneurons through an antigen-antibody interaction and modulated synaptic transmission. Immunoreactivity against nerve terminals showed strong correlation with synaptic modulation ability. In addition, several controls have ruled out the possibility for this synaptic modulation to be mediated through proteases or nonspecific effects. Effective IgG potentiated both spontaneous and asynchronous transmitter release. Application of pharmacological inhibitors suggested that activation of this increased release required a nonconstitutive Ca2+ influx through N-type (
Cav2.2
) channels and
phospholipase C
activity and that activation of IP3 and ryanodine receptors were necessary to both activate and sustain the increased release. Consistent with the notion that ALS is heterogeneous disorder, our results reveal that, in approximately 50% of ALS patients, motor nerve terminals constitutes a target for autoimmune response.
...
PMID:Calcium signaling pathways mediating synaptic potentiation triggered by amyotrophic lateral sclerosis IgG in motor nerve terminals. 1652 45
ADP and other nucleotides control ion currents in the nervous system via various P2Y receptors. In this respect, Cav2 and Kv7 channels have been investigated most frequently. The fine tuning of neuronal ion channel gating via G protein coupled receptors frequently relies on the formation of higher order protein complexes that are organized by scaffolding proteins and harbor receptors and channels together with interposed signaling components. However, ion channel complexes containing P2Y receptors have not been described. Therefore, the regulation of
Cav2.2
and Kv7.2/7.3 channels via P2Y1 and P2Y12 receptors and the coordination of these ion channels and receptors in the plasma membranes of tsA 201 cells have been investigated here. ADP inhibited currents through
Cav2.2
channels via both P2Y1 and P2Y12 receptors with
phospholipase C
and pertussis toxin-sensitive G proteins being involved, respectively. The nucleotide controlled the gating of Kv7 channels only via P2Y1 and
phospholipase C
. In fluorescence energy transfer assays using conventional as well as total internal reflection (TIRF) microscopy, both P2Y1 and P2Y12 receptors were found juxtaposed to
Cav2.2
channels, but only P2Y1, and not P2Y12, was in close proximity to Kv7 channels. Using fluorescence recovery after photobleaching in TIRF microscopy, evidence for a physical interaction was obtained for the pair P2Y12/
Cav2.2
, but not for any other receptor/channel combination. These results reveal a membrane juxtaposition of P2Y receptors and ion channels in parallel with the control of neuronal ion currents by ADP. This juxtaposition may even result in apparent physical interactions between receptors and channels.
...
PMID:Membrane coordination of receptors and channels mediating the inhibition of neuronal ion currents by ADP. 2717 14
Agmatine suppresses peripheral sympathetic tone by modulating
Cav2.2
channels in peripheral sympathetic neurons. However, the detailed cellular signaling mechanism underlying the agmatine-induced
Cav2.2
inhibition remains unclear. Therefore, in the present study, we investigated the electrophysiological mechanism for the agmatine-induced inhibition of
Cav2.2
current (I
Cav2.2
) in rat celiac ganglion (CG) neurons. Consistent with previous reports, agmatine inhibited I
Cav2.2
in a VI manner. The agmatine-induced inhibition of the I
Cav2.2
current was also almost completely hindered by the blockade of the imidazoline I
2
receptor (IR
2
), and an IR
2
agonist mimicked the inhibitory effect of agmatine on I
Cav2.2
, implying involvement of IR
2
. The agmatine-induced I
Cav2.2
inhibition was significantly hampered by the blockade of G protein or
phospholipase C
(
PLC
), but not by the pretreatment with pertussis toxin. In addition, diC8-phosphatidylinositol 4,5-bisphosphate (PIP
2
) dialysis nearly completely hampered agmatine-induced inhibition, which became irreversible when PIP
2
resynthesis was blocked. These results suggest that in rat peripheral sympathetic neurons, agmatine-induced IR
2
activation suppresses
Cav2.2
channel voltage-independently, and that the
PLC
-dependent PIP
2
hydrolysis is responsible for the agmatine-induced suppression of the
Cav2.2
channel.
...
PMID:Phospholipase C-dependent hydrolysis of phosphatidylinositol 4,5-bisphosphate underlies agmatine-induced suppression of N-type Ca
2+
channel in rat celiac ganglion neurons. 2813 38
