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Target Concepts:
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Query: EC:2.7.10.1 (
ERK
)
95,504
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Postural orthostatic tachycardia syndrome
(POTS) is a common autonomic disorder of largely unknown etiology that presents with sustained tachycardia on standing, syncope and elevated norepinephrine spillover. Some individuals with POTS experience anxiety, depression and cognitive dysfunction. Previously, we identified a mutation, A457P, in the norepinephrine (NE; also known as noradrenaline) transporter (
NET
; encoded by SLC6A2) in POTS patients.
NET
is expressed at presynaptic sites in NE neurons and plays a crucial role in regulating NE signaling and homeostasis through NE reuptake into noradrenergic nerve terminals. Our in vitro studies demonstrate that A457P reduces both
NET
surface trafficking and NE transport and exerts a dominant-negative impact on wild-type
NET
proteins. Here we report the generation and characterization of
NET
A457P mice, demonstrating the ability of A457P to drive the POTS phenotype and behaviors that are consistent with reported comorbidities. Mice carrying one A457P allele (
NET
(+/P)) exhibited reduced brain and sympathetic NE transport levels compared with wild-type (
NET
(+/+)) mice, whereas transport activity in mice carrying two A457P alleles (
NET
(P/P)) was nearly abolished.
NET
(+/P) and
NET
(P/P) mice exhibited elevations in plasma and urine NE levels, reduced 3,4-dihydroxyphenylglycol (DHPG), and reduced DHPG:NE ratios, consistent with a decrease in sympathetic nerve terminal NE reuptake. Radiotelemetry in unanesthetized mice revealed tachycardia in
NET
(+/P) mice without a change in blood pressure or baroreceptor sensitivity, consistent with studies of human
NET
A457P carriers.
NET
(+/P) mice also demonstrated behavioral changes consistent with CNS
NET
dysfunction. Our findings support that
NET
dysfunction is sufficient to produce a POTS phenotype and introduces the first genetic model suitable for more detailed mechanistic studies of the disorder and its comorbidities.
...
PMID:Norepinephrine transporter variant A457P knock-in mice display key features of human postural orthostatic tachycardia syndrome. 2358 Feb 1
