期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 101, 期 23, 页码 8762-8767出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0401667101
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资金
- NCI NIH HHS [P30 CA068485, CA68485] Funding Source: Medline
- NHLBI NIH HHS [HL56693, P01 HL056693] Funding Source: Medline
- NICHD NIH HHS [P30 HD015052, HD15052] Funding Source: Medline
- NIDDK NIH HHS [P30 DK020593, P60 DK020593, DK20593] Funding Source: Medline
- NIMH NIH HHS [MH58921, R01 MH058921] Funding Source: Medline
- NINDS NIH HHS [P01 NS034448, NS34448] Funding Source: Medline
Presynaptic acetylcholine (ACh) synthesis and release is thought to be sustained by a hemicholinium-3-sensitive choline transporter (CHT). We disrupted the murine CHT gene and examined CHT-/- and +/- animals for evidence of impaired cholinergic neurotransmission. Although morphologically normal at birth, CHT-/- mice become immobile, breathe irregularly, appear cyanotic, and die within an hour. Hemicholinium-3-sensitive choline uptake and subsequent ACh synthesis are specifically lost in CHT-/- mouse brains. Moreover, we observe a time-dependent loss of spontaneous and evoked responses at CHT-/- neuromuscular junctions. Consistent with deficits in synaptic ACh availability, we also observe developmental alterations in neuromuscular junction morphology reminiscent of changes in mutants lacking ACh synthesis. Adult CHT+/- mice overcome reductions in CHT protein levels and sustain choline uptake activity at wild-type levels through posttranslational mechanisms. Our results demonstrate that CHT is an essential and regulated presynaptic component of cholinergic signaling and indicate that CHT warrants consideration as a candidate gene for disorders characterized by cholinergic hypofunction.
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