Title:GIRK2 Channels in Down Syndrome and Alzheimer’s Disease
Volume: 19
Issue: 12
关键词:
唐氏综合症，阿尔茨海默病，GIRK2通道，遗传疾病，神经元多动，KCNJ6。
摘要: Cognitive impairment in Down syndrome (DS) results from the abnormal expression of
hundreds of genes. However, the impact of KCNJ6, a gene located in the middle of the ‘Down syndrome
critical region’ of chromosome 21, seems to stand out. KCNJ6 encodes GIRK2 (KIR3.2) subunits
of G protein-gated inwardly rectifying potassium channels, which serve as effectors for GABAB,
m2, 5HT1A, A1, and many other postsynaptic metabotropic receptors. GIRK2 subunits are heavily
expressed in neocortex, cerebellum, and hippocampus. By controlling resting membrane potential and
neuronal excitability, GIRK2 channels may thus affect both synaptic plasticity and stability of neural
circuits in the brain regions important for learning and memory. Here, we discuss recent experimental
data regarding the role of KCNJ6/GIRK2 in neuronal abnormalities and cognitive impairment in models
of DS and Alzheimer’s disease (AD). The results compellingly show that signaling through
GIRK2 channels is abnormally enhanced in mouse genetic models of Down syndrome and that partial
suppression of GIRK2 channels with pharmacological or genetic means can restore synaptic plasticity
and improve impaired cognitive functions. On the other hand, signaling through GIRK2 channels is
downregulated in AD models, such as models of early amyloidopathy. In these models, reduced
GIRK2 channel signaling promotes neuronal hyperactivity, causing excitatory-inhibitory imbalance
and neuronal death. Accordingly, activation of GABAB/GIRK2 signaling by GIRK channel activators
or GABAB receptor agonists may reduce Aβ-induced hyperactivity and subsequent neuronal death,
thereby exerting a neuroprotective effect in models of AD.
