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Hyperpolarization-activated, cyclic nucleotide-sensitive (HCN) channels are key regulators of subthreshold membrane potentials in excitable cells. The four mammalian HCN channel isoforms, HCN1-HCN4, are expressed throughout the body, where they contribute to diverse physiological processes including cardiac pacemaking, sleep-wakefulness cycles, memory, and somatic sensation. While all HCN channel isoforms produce currents when expressed by themselves, an emerging list of interacting proteins shape HCN channel excitability to influence the physiologically relevant output. The best studied of these regulatory proteins is the auxiliary subunit, TRIP8b, which binds to multiple sites in the C-terminus of the HCN channels to regulate expression and disrupt cAMP binding to fine-tune neuronal HCN channel excitability. Less is known about the mechanisms of action of other HCN channel interaction partners like filamin A, Src tyrosine kinase, and MinK-related peptides, which have a range of effects on HCN channel gating and expression. More recently, the inositol trisphosphate receptor-associated cGMP-kinase substrates IRAG1 and LRMP (also known as IRAG2), were discovered as specific regulators of the HCN4 isoform. This review summarizes the known protein interaction partners of HCN channels and their mechanisms of action and identifies gaps in our knowledge. [ABSTRACT FROM AUTHOR]

Hyperpolarization-activated, cyclic nucleotide-sensitive (HCN) channels are key regulators of subthreshold membrane potentials in excitable cells. The four mammalian HCN channel isoforms, HCN1-HCN4, are expressed throughout the body, where they contribute to diverse physiological processes including cardiac pacemaking, sleep-wakefulness cycles, memory, and somatic sensation. While all HCN channel isoforms produce currents when expressed by themselves, an emerging list of interacting proteins shape HCN channel excitability to influence the physiologically relevant output. The best studied of these regulatory proteins is the auxiliary subunit, TRIP8b, which binds to multiple sites in the C-terminus of the HCN channels to regulate expression and disrupt cAMP binding to fine-tune neuronal HCN channel excitability. Less is known about the mechanisms of action of other HCN channel interaction partners like filamin A, Src tyrosine kinase, and MinK-related peptides, which have a range of effects on HCN channel gating and expression. More recently, the inositol trisphosphate receptor-associated cGMP-kinase substrates IRAG1 and LRMP (also known as IRAG2), were discovered as specific regulators of the HCN4 isoform. This review summarizes the known protein interaction partners of HCN channels and their mechanisms of action and identifies gaps in our knowledge.

The shape of the cardiac action potential (AP) is determined by the contributions of numerous ion channels. Any dysfunction in the proper function or expression of these ion channels can result in a change in effective refractory period (ERP) and lead to arrhythmia. The processes underlying the correct targeting of ion channels to the plasma membrane are complex, and have not been fully characterized in cardiac myocytes. Emerging evidence highlights ion channel trafficking as a potential causative factor in certain acquired and inherited arrhythmias, and therapies which target trafficking as opposed to pore block are starting to receive attention. In this review we present the current evidence for the mechanisms which underlie precise control of cardiac ion channel trafficking and targeting.

The shape of the cardiac action potential (AP) is determined by the contributions of numerous ion channels. Any dysfunction in the proper function or expression of these ion channels can result in a change in effective refractory period (ERP) and lead to arrhythmia. The processes underlying the correct targeting of ion channels to the plasma membrane are complex, and have not been fully characterized in cardiac myocytes. Emerging evidence highlights ion channel trafficking as a potential causative factor in certain acquired and inherited arrhythmias, and therapies which target trafficking as opposed to pore block are starting to receive attention. In this review we present the current evidence for the mechanisms which underlie precise control of cardiac ion channel trafficking and targeting. [ABSTRACT FROM AUTHOR]

Heterotrimeric G-proteins play a fundamentally important role in regulating signal transduction pathways in the kidney. Accessory proteins are being identified as direct binding partners for heterotrimeric G-protein α or βγ subunits to promote more diverse mechanisms by which G-protein signaling is controlled. In some instances, accessory proteins can modulate the signaling magnitude, localization, and duration following the activation of cell membrane-associated receptors. Alternatively, accessory proteins complexed with their G-protein α or βγ subunits can promote non-canonical models of signaling activity within the cell. In this review, we will highlight the expression profile, localization and functional importance of these newly identified accessory proteins to control the function of select G-protein subunits under normal and various disease conditions observed in the kidney.

Heterotrimeric G-proteins play a fundamentally important role in regulating signal transduction pathways in the kidney. Accessory proteins are being identified as direct binding partners for heterotrimeric G-protein α or βγ subunits to promote more diverse mechanisms by which G-protein signaling is controlled. In some instances, accessory proteins can modulate the signaling magnitude, localization, and duration following the activation of cell membrane-associated receptors. Alternatively, accessory proteins complexed with their G-protein α or βγ subunits can promote non-canonical models of signaling activity within the cell. In this review, we will highlight the expression profile, localization and functional importance of these newly identified accessory proteins to control the function of select G-protein subunits under normal and various disease conditions observed in the kidney. [ABSTRACT FROM AUTHOR]