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:2.3.1.108 (
TAT
)
2,389
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The voltage-gated K
+
channel
Kv2.1
has been intimately linked with neuronal apoptosis. After ischemic, oxidative, or inflammatory insults,
Kv2.1
mediates a pronounced, delayed enhancement of K
+
efflux, generating an optimal intracellular environment for caspase and nuclease activity, key components of programmed cell death. This apoptosis-enabling mechanism is initiated via Zn
2+
-dependent dual phosphorylation of
Kv2.1
, increasing the interaction between the channel's intracellular C-terminus domain and the SNARE (soluble
N
-ethylmaleimide-sensitive factor activating protein receptor) protein syntaxin 1A. Subsequently, an upregulation of
de novo
channel insertion into the plasma membrane leads to the critical enhancement of K
+
efflux in damaged neurons. Here, we investigated whether a strategy designed to interfere with the cell death-facilitating properties of
Kv2.1
, specifically its interaction with syntaxin 1A, could lead to neuroprotection following ischemic injury
in vivo
The minimal syntaxin 1A-binding sequence of
Kv2.1
C terminus (C1aB) was first identified via a far-Western peptide screen and used to create a protherapeutic product by conjugating C1aB to a cell-penetrating domain. The resulting peptide (
TAT
-C1aB) suppressed enhanced whole-cell K
+
currents produced by a mutated form of
Kv2.1
mimicking apoptosis in a mammalian expression system, and protected cortical neurons from slow excitotoxic injury
in vitro
, without influencing NMDA-induced intracellular calcium responses. Importantly, intraperitoneal administration of
TAT
-C1aB in mice following transient middle cerebral artery occlusion significantly reduced ischemic stroke damage and improved neurological outcome. These results provide strong evidence that targeting the proapoptotic function of
Kv2.1
is an effective and highly promising neuroprotective strategy.
SIGNIFICANCE STATEMENT
Kv2.1
is a critical regulator of apoptosis in central neurons. It has not been determined, however, whether the cell death-enabling function of this K
+
channel can be selectively targeted to improve neuronal survival following injury
in vivo
The experiments presented here demonstrate that the cell death-specific role of
Kv2.1
can be uniquely modulated to provide neuroprotection in an animal model of acute ischemic stroke. We thus reveal a novel therapeutic strategy for neurological disorders that are accompanied by
Kv2.1
-facilitated forms of cell death.
...
PMID:Targeting a Potassium Channel/Syntaxin Interaction Ameliorates Cell Death in Ischemic Stroke. 2848 76
Kv2.1
channels mediate cell death-enabling loss of cytosolic potassium in neurons following plasma membrane insertion at somatodendritic clusters. Overexpression of the carboxyl terminus (CT) of the cognate channel Kv2.2 is neuroprotective by disrupting
Kv2.1
surface clusters. Here, we define a seven-amino acid declustering domain within Kv2.2 CT (DP-2) and demonstrate its neuroprotective efficacy in a murine ischemia-reperfusion model.
TAT
-DP-2, a membrane-permeable derivative, induces
Kv2.1
surface cluster dispersal, prevents post-injurious pro-apoptotic potassium current enhancement, and is neuroprotective in vitro by disrupting the association of
Kv2.1
with VAPA.
TAT
-DP-2 also induces
Kv2.1
cluster dispersal in vivo in mice, reducing infarct size and improving long-term neurological function following stroke. We suggest that
TAT
-DP-2 induces
Kv2.1
declustering by disrupting
Kv2.1
-VAPA association and scaffolding sites required for the membrane insertion of
Kv2.1
channels following injury. We present the first evidence of targeted disruption of
Kv2.1
-VAPA association as a neuroprotective strategy following brain ischemia.
...
PMID:Targeted disruption of Kv2.1-VAPA association provides neuroprotection against ischemic stroke in mice by declustering Kv2.1 channels. 3293 50
