Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
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Target Concepts:
Gene/Protein
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Query: EC:2.7.11.17 (
CaMKII
)
4,029
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The efficacy of (131)I-metaiodobenzylguanidine (MIBG) therapy relies on
norepinephrine transporter
(
NET
) function. The ionic make-up of the extracellular fluid critically controls neuronal cell activity and can also affect substrate transport. In this study, we explored the effect of treatment with elevated KCl concentration on MIBG uptake in SK-N-SH neuroblastoma cells. KCl stimulation caused a rapid increase of (131)I-MIBG uptake in a manner that was calcium-dependent and accompanied by activation of calcium/calmodulin-dependent protein kinase (CaMK)II. The effect was completely abolished by KN93, an inhibitor of
CaMKI
, II, and IV. STO609, a selective inhibitor of CaMK kinase required for activation of
CaMKI
and IV, but not
CaMKII
, only modestly attenuated the response. The KCl effect was also completely abrogated by ML7, a selective inhibitor of myosin light chain kinase (MLCK). This restricted form of CaMK activates myosin, which is required for vesicle trafficking. Saturation kinetic analysis revealed KCl stimulation to increase maximal transport velocity without affecting substrate affinity. In conclusion, KCl stimulation rapidly upregulates
NET
function through the CaMK pathway via activation of
CaMKII
and MLCK. These findings allow a better understanding of how
NET
function is acutely modulated by the ionic environment, which in turn may ultimately help improve the efficacy of (131)I-MIBG therapy.
...
PMID:131I-MIBG targeting of neuroblastoma cells is acutely enhanced by KCl stimulation through the calcium/calmodulin-dependent kinase pathway. 2376 46
Amphetamines and amphetamine-derivatives elevate neurotransmitter concentrations by competing with endogenous biogenic amines for reuptake. In addition, AMPHs have been shown to activate endocytosis of the dopamine transporter (DAT) which further elevates extracellular dopamine (DA). We previously found that the biochemical cascade leading to this cellular process involves entry of AMPH into the cell through the DAT, stimulation of an intracellular trace amine-associated receptor, TAAR1, and activation of the small GTPase, RhoA. We also showed that the neuronal glutamate transporter, EAAT3, undergoes endocytosis via the same cascade in DA neurons, leading to potentiation of glutamatergic inputs. Since AMPH is a transported inhibitor of both DAT and the
norepinephrine transporter
(
NET
), and EAAT3 is also expressed in norepinephrine (NE) neurons, we explored the possibility that this signaling cascade occurs in NE neurons. We found that AMPH can cause endocytosis of
NET
as well as EAAT3 in NE neurons.
NET
endocytosis is dependent on TAAR1, RhoA, intracellular calcium and
CaMKII
activation, similar to DAT. However, EAAT3 endocytosis is similar in all regards except its dependence upon
CaMKII
activation. RhoA activation is dependent on calcium, but not
CaMKII
, explaining a divergence in AMPH-mediated endocytosis of DAT and
NET
from that of EAAT3. These data indicate that AMPHs and other TAAR1 agonists can affect glutamate signaling through internalization of EAAT3 in NE as well as DA neurons.
...
PMID:Amphetamine Stimulates Endocytosis of the Norepinephrine and Neuronal Glutamate Transporters in Cultured Locus Coeruleus Neurons. 3191 66
