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3',5'-cyclic AMP activates HCN4. 57 / 58
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"Finally, unlike TRIP8b, which competes with cAMP for binding to the CNBD (Zolles et al., 2009; Santoro et al., 2011; Bankston et al., 2012, 2017; DeBerg et al., 2015), LRMP and IRAG allow cAMP to bind, as evidenced by cAMP-dependent slowing of HCN4 deactivation in the presence of LRMP or IRAG (Liao et al., 2012; Peters et al., 2020a)."
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"Moreover, chronically decreased cAMP via Gi-DREADD stimulation leads to an increase in I h in VTA dopamine neurons and enhanced binding of HCN3/HCN4 with tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b), an auxiliary subunit that is known to facilitate HCN channel surface trafficking."
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"These results indicate that the ER transmembrane and luminal domains of LRMP are not required for regulation of HCN4 and they support the idea that LRMP limits cAMP potentiation of HCN4 by interfering with a downstream step in the cAMP signal transduction pathway.To further resolve which regions of LRMP are required to regulate HCN4, we tested a series of additional truncated LRMP constructs (shown schematically in Figure 2A, Figure 2—figure supplement 1) for their ability to prevent cAMP-dependent shifts in HCN4 activation."
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"Most importantly, also, HCN4R669Q mice are embryonically lethal, which strongly suggests that basal cAMP-dependent activation of HCN4 is a general prerequisite for the physiological function of the channel and that preventing CDR alone has similar functional effects as complete knockout of HCN4."
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"After the confirmation of reproducibility for 1200 compounds with more than 30% inhibition at 30 μM, intracellular cAMP was measured in hHCN4-expressing cells incubated in the presence of the compounds, to eliminate those that regulate cAMP signaling, because intracellular cAMP directly regulates HCN4 activity; however, this concern was proven to be unfounded (data not shown)."
eidos
"Specifically , cAMP-dependent increase of HCN4-mediated current was believed to be required for the acceleration of the HR upon high activity of the sympathetic division of the ANS , whereas a drop in cAMP levels following vagal stimulation would decrease HCN4 activity and slow down the HR5 ,6,9 ."
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"These results indicate that the ER transmembrane and luminal domains of LRMP are not required for regulation of HCN4 and they support the idea that LRMP limits cAMP potentiation of HCN4 by interfering with a downstream step in the cAMP signal transduction pathway.To further resolve which regions of LRMP are required to regulate HCN4, we tested a series of additional truncated LRMP constructs (shown schematically in Fig. 2A) for their ability to prevent cAMP-dependent shifts in HCN4 activation."
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"For instance, it has been shown that in Chinese hamster ovary (CHO) cells external application of cAMP did not increase HCN4 channel activity in both whole-cell recordings and excised patches as the basal voltage dependence was already shifted to more depolarized potentials [XREF_BIBR]."
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"Since β‐adrenergic signaling increases the production of cAMP which enhances gating of Hcn4 ion channels as well as intracellular Ca cycling,41, 42 it is unclear what molecular determinants are responsible for the contrasting effects of isoproterenol treatment (Figure 6b, (i)–(iii))."
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"Here, we utilize comparative S672R versus WT NMR analyses to show that the S672R mutation results in extensive perturbations of the dynamics in both apo- and holo-forms of the HCN4 isoform, reflecting how S672R remodels the free energy landscape for the modulation of HCN4 by cAMP, i.e. the primary cyclic nucleotide modulator of HCN channels."
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"These domains contribute to the potentiation of HCN4 channels by cAMP (Wainger et al., 2001; Zagotta et al., 2003; Xu et al., 2010; Akimoto et al., 2014; Porro et al., 2019; Page et al., 2020), increasing heart rate (HR) in response to the β-adrenergic response (Brown et al., 1979; DiFrancesco and Tortora, 1991; Ono et al., 1993; Schweizer et al., 2010)."