The structure of the apo <scp>cAMP</scp>‐binding domain of <scp>HCN</scp>4 – a stepping stone toward understanding the <scp>cAMP</scp>‐dependent modulation of the hyperpolarization‐activated cyclic‐nucleotide‐gated ion channels

Akimoto, Madoka; VanSchouwen, Bryan; Melacini, Giuseppe

doi:10.1111/febs.14408

Cited by 10 publications

(10 citation statements)

References 54 publications

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“…1 d), which interconvert in the fast exchange regime, as previously shown (15). cAMP-binding selects and stabilizes the active state (26,39), whereas cAMP analogs modulate the position of the autoinhibitory versus active P 1 5 P 2 equilibrium. Such modulations correlate with the cNMP-dependent changes in activation voltages (DV 1/2 ) measured by electrophysiology for integral full-length ion channels (15).…”

Section: Introductionsupporting

confidence: 59%

Allosteric Mechanisms of Nonadditive Substituent Contributions to Protein-Ligand Binding

Boulton

Van

VanSchouwen

et al. 2020

Biophysical Journal

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Quantifying chemical substituent contributions to ligand-binding free energies is challenging due to nonadditive effects. Protein allostery is a frequent cause of nonadditivity, but the underlying allosteric mechanisms often remain elusive.Here, we propose a general NMR-based approach to elucidate such mechanisms and we apply it to the HCN4 ion channel, whose cAMP-binding domain is an archetypal conformational switch. Using NMR, we show that nonadditivity arises not only from concerted conformational transitions, but also from conformer-specific effects, such as steric frustration. Our results explain how affinity-reducing functional groups may lead to affinity gains if combined. Surprisingly, our approach also reveals that nonadditivity depends markedly on the receptor conformation. It is negligible for the inhibited state but highly significant for the active state, opening new opportunities to tune potency and agonism of allosteric effectors.

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Section: Introductionsupporting

confidence: 59%

Allosteric Mechanisms of Nonadditive Substituent Contributions to Protein-Ligand Binding

Boulton

Van

VanSchouwen

et al. 2020

Biophysical Journal

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“…In small dorsal root ganglia neurons, PGE 2 -evoked activation of HCN-mediated current and depolarization of resting membrane potential via EP 3 (Sachs et al., 2009) is inhibited by activation of GPR35, a Gi/o-coupled receptor that reduces intracellular cAMP levels (Resta et al., 2016). It is known that cAMP can bind to the cyclic nucleotide-binding domain of the HCN3 (Akimoto et al., 2018) and activate it (Robichaux and Cheng, 2018). In our preliminary study, we have found that PD reduces the expression of catalytic subunit of protein kinase A in oxytocin neurons (Li et al., unpublished data).…”

Section: Discussionmentioning

confidence: 99%

Involvement of Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel 3 in Oxytocin Neuronal Activity in Lactating Rats With Pup Deprivation

Liu

et al. 2020

ASN Neuro

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Oxytocin, a hypothalamic neuropeptide essential for breastfeeding, is mainly produced in oxytocin neurons in the supraoptic nucleus (SON) and paraventricular nucleus. However, mechanisms underlying oxytocin secretion, specifically the involvement of hyperpolarization-activated cyclic nucleotide-gated channel 3 (HCN3) in oxytocin neuronal activity, remain unclear. Using a rat model of intermittent and continuous pup deprivation (PD) at the middle stage of lactation, we analyzed the contribution of HCN3 in oxytocin receptor (OTR)-associated signaling cascade to oxytocin neuronal activity in the SON. PD caused maternal depression, anxiety, milk shortage, involution of the mammary glands, and delays in uterine recovery, particularly in continuous PD. PD increased hypothalamic but not plasma oxytocin levels in enzyme-linked immunosorbent assay. In the SON, PD increased c-Fos expression but reduced expressions of cyclooxygenase-2 and HCN3 in Western blots and/or immunohistochemistry. Moreover, PD significantly increased the molecular association of OTR with HCN3 in coimmunoprecipitation. In brain slices, inhibition of HCN3 activity with DK-AH269 blocked prostaglandin E2-evoked increase in the firing activity and burst discharge in oxytocin neurons in patch-clamp recordings. In addition, oxytocin-evoked increase in the molecular association between OTR and HCN3 in brain slices of the SON was blocked by pretreatment with indomethacin, an inhibitor of cyclooxygenase-2. These results indicate that normal activity of oxytocin neurons is under the regulation of an oxytocin receptor–cyclooxygenase-2–HCN3 pathway and that PD disrupts maternal behavior through increasing intranuclear oxytocin secretion in the SON but likely reducing bolus oxytocin release into the blood through inhibition of HCN3 activity.

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“…EPACs also regulate several physiological mechanisms including cellular secretion, adhesion and differentiation [ 22 ]. Finally, the cAMP binding domain has been identified at cyclic nucleotide-gated ion channels; cAMP-mediated channels’ stimulation remains of paramount importance for neuronal impulse transmission and cardiomyocyte contractility [ 29 ].…”

Section: Camp Signalingmentioning

confidence: 99%

Cyclic AMP Signaling in Biliary Proliferation: A Possible Target for Cholangiocarcinoma Treatment?

Baiocchi

Lenci

Mihalj

et al. 2021

Cells

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Cholangiocarcinoma is a lethal disease with scarce response to current systemic therapy. The rare occurrence and large heterogeneity of this cancer, together with poor knowledge of its molecular mechanisms, are elements contributing to the difficulties in finding an appropriate cure. Cholangiocytes (and their cellular precursors) are considered the liver component giving rise to cholangiocarcinoma. These cells respond to several hormones, neuropeptides and molecular stimuli employing the cAMP/PKA system for the translation of messages in the intracellular space. For instance, in physiological conditions, stimulation of the secretin receptor determines an increase of intracellular levels of cAMP, thus activating a series of molecular events, finally determining in bicarbonate-enriched choleresis. However, activation of the same receptor during cholangiocytes’ injury promotes cellular growth again, using cAMP as the second messenger. Since several scientific pieces of evidence link cAMP signaling system to cholangiocytes’ proliferation, the possible changes of this pathway during cancer growth also seem relevant. In this review, we summarize the current findings regarding the cAMP pathway and its role in biliary normal and neoplastic cell proliferation. Perspectives for targeting the cAMP machinery in cholangiocarcinoma therapy are also discussed.

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The structure of the apo cAMP‐binding domain of HCN4 – a stepping stone toward understanding the cAMP‐dependent modulation of the hyperpolarization‐activated cyclic‐nucleotide‐gated ion channels

Cited by 10 publications

References 54 publications

Allosteric Mechanisms of Nonadditive Substituent Contributions to Protein-Ligand Binding

Allosteric Mechanisms of Nonadditive Substituent Contributions to Protein-Ligand Binding

Involvement of Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel 3 in Oxytocin Neuronal Activity in Lactating Rats With Pup Deprivation

Cyclic AMP Signaling in Biliary Proliferation: A Possible Target for Cholangiocarcinoma Treatment?

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