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Activity-dependent transcriptional regulation of M-Type (Kv7) K(+) channels by AKAP79/150-mediated NFAT actions.

ABSTRACT: M-type K(+) channels, encoded by KCNQ2-KCNQ5 genes, play key roles in regulation of neuronal excitability; however, less is known about the mechanisms controlling their transcriptional expression. Here, we discovered a mechanism regulating KCNQ2/3 transcriptional expression by neuronal activity in rodent neurons, involving activation of calcineurin and nuclear factor of activated T cell (NFAT) transcription factors, orchestrated by A kinase-anchoring protein (AKAP)79/150. The signal requires Ca(2+) influx through L-type Ca(2+) channels and both local and global Ca(2+) elevations. We postulate increased M-channel expression to act as a negative feedback to suppress neuronal hyperexcitability, demonstrated by profoundly upregulated KCNQ2/3 transcription in hippocampi from wild-type, but not AKAP150(-/-), mice after drug-induced seizures. Thus, we suggest a distinct role of AKAP79/150 and the complex it organizes in activity-dependent M-channel transcription, which may potentially serve throughout the nervous system to limit overexcitability associated with disease states such as epilepsy.

SUBMITTER: Zhang J

PROVIDER: S-EPMC3707625 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Activity-dependent transcriptional regulation of M-Type (Kv7) K(+) channels by AKAP79/150-mediated NFAT actions.

Zhang Jie J Shapiro Mark S MS

Neuron 20121201 6

M-type K(+) channels, encoded by KCNQ2-KCNQ5 genes, play key roles in regulation of neuronal excitability; however, less is known about the mechanisms controlling their transcriptional expression. Here, we discovered a mechanism regulating KCNQ2/3 transcriptional expression by neuronal activity in rodent neurons, involving activation of calcineurin and nuclear factor of activated T cell (NFAT) transcription factors, orchestrated by A kinase-anchoring protein (AKAP)79/150. The signal requires Ca( ...[more]

PMID: 23259949

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Project description:M-type channels are localized to neuronal, cardiovascular, and epithelial tissues, where they play critical roles in control of excitability and K(+) transport, and are regulated by numerous receptors via G(q/11)-mediated signals. One pathway shown for KCNQ2 and muscarinic receptors uses PKC, recruited to the channels by A-kinase anchoring protein (AKAP)79/150. As M-type channels can be variously composed of KCNQ1-5 subunits, and M current is known to be regulated by Ca(2+)/calmodulin (CaM) and PIP(2), we probed the generality of AKAP79/150 actions among KCNQ1-5 channels, and the influence of Ca(2+)/CaM and PIP(2) on AKAP79/150 actions. We first examined which KCNQ subunits are targeted by AKAP79 in Chinese hamster ovary (CHO) cells heterologously expressing KCNQ1-5 subunits and AKAP79, using fluorescence resonance energy transfer (FRET) under total internal reflection fluorescence (TIRF) microscopy, and patch-clamp analysis. Donor-dequenching FRET between CFP-tagged KCNQ1-5 and YFP-tagged AKAP79 revealed association of KCNQ2-5, but not KCNQ1, with AKAP79. In parallel with these results, CHO cells stably expressing M(1) receptors studied under perforated patch-clamp showed cotransfection of AKAP79 to "sensitize" KCNQ2/3 heteromers and KCNQ2-5, but not KCNQ1, homomers to muscarinic inhibition, manifested by shifts in the dose-response relations to lower concentrations. The effect on KCNQ4 was abolished by the T553A mutation of the putative PKC phosphorylation site. We then probed the role of CaM and PIP(2) in these AKAP79 actions. TIRF/FRET experiments revealed cotransfection of wild-type, but not dominant-negative (DN), CaM that cannot bind Ca(2+), to disrupt the interaction of YFP-tagged AKAP79(1-153) with CFP-tagged KCNQ2-5. Tonic depletion of PIP(2) by cotransfection of a PIP(2) phosphatase had no effect, and sudden depletion of PIP(2) did not delocalize GFP-tagged AKAP79 from the membrane. Finally, patch-clamp experiments showed cotransfection of wild-type, but not DN, CaM to prevent the AKAP79-mediated sensitization of KCNQ2/3 heteromers to muscarinic inhibition. Thus, AKAP79 acts on KCNQ2-5, but not KCNQ1-containing channels, with effects disrupted by calcified CaM, but not by PIP(2) depletion.

Project description:Lung diseases constitute a global health concern causing disability. According to WHO in 2016, respiratory diseases accounted for 24% of world population mortality, the second cause of death after cardiovascular diseases. The Kv7 channels family is a group of voltage-dependent K+ channels (Kv) encoded by KCNQ genes that are involved in various physiological functions in numerous cell types, especially, cardiac myocytes, smooth muscle cells, neurons, and epithelial cells. Kv7 channel α-subunits are regulated by KCNE1-5 ancillary β-subunits, which modulate several characteristics of Kv7 channels such as biophysical properties, cell-location, channel trafficking, and pharmacological sensitivity. Kv7 channels are mainly expressed in two large groups of lung tissues: pulmonary arteries (PAs) and bronchial tubes. In PA, Kv7 channels are expressed in pulmonary artery smooth muscle cells (PASMCs); while in the airway (trachea, bronchus, and bronchioles), Kv7 channels are expressed in airway smooth muscle cells (ASMCs), airway epithelial cells (AEPs), and vagal airway C-fibers (VACFs). The functional role of Kv7 channels may vary depending on the cell type. Several studies have demonstrated that the impairment of Kv7 channel has a strong impact on pulmonary physiology contributing to the pathophysiology of different respiratory diseases such as cystic fibrosis, asthma, chronic obstructive pulmonary disease, chronic coughing, lung cancer, and pulmonary hypertension. Kv7 channels are now recognized as playing relevant physiological roles in many tissues, which have encouraged the search for Kv7 channel modulators with potential therapeutic use in many diseases including those affecting the lung. Modulation of Kv7 channels has been proposed to provide beneficial effects in a number of lung conditions. Therefore, Kv7 channel openers/enhancers or drugs acting partly through these channels have been proposed as bronchodilators, expectorants, antitussives, chemotherapeutics and pulmonary vasodilators.

Dataset Information

Activity-dependent transcriptional regulation of M-Type (Kv7) K(+) channels by AKAP79/150-mediated NFAT actions.

Publications

Activity-dependent transcriptional regulation of M-Type (Kv7) K(+) channels by AKAP79/150-mediated NFAT actions.

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