Bioartificial Sinus Node Constructed via In Vivo Gene Transfer of an Engineered Pacemaker HCN Channel Reduces the Dependence on Electronic Pacemaker in a Sick-Sinus Syndrome Model

Tse, Hung Fat; Xue, Tian; Lau, Chu Pak; Siu, Chung Wah; Wang, Kai; Zhang, Qing Yong; Tomaselli, Gordon F.; Akar, Fadi G.; Tse, Gary

doi:10.1161/circulationaha.106.615385

Cited by 142 publications

(144 citation statements)

References 38 publications

Supporting

Mentioning

140

Contrasting

Order By: Relevance

“…2). Understanding how cAMP regulates HCN channels is important because gene transfer of engineered HCN channels has shown promise for treating sick-sinus syndrome (3). Unlike the soluble receptors, HCN channels have an efficient mechanism for activation without cAMP, through hyperpolarization of the membrane potential.…”

mentioning

confidence: 99%

Cytoplasmic cAMP-sensing domain of hyperpolarization-activated cation (HCN) channels uses two structurally distinct mechanisms to regulate voltage gating

Wicks

Wong²,

Sun³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Voltage gating of hyperpolarization-activated cation (HCN) channels is potentiated by direct binding of cAMP to a cytoplasmic cAMP-sensing domain (CSD). When unliganded, the CSD inhibits hyperpolarization-dependent opening of the HCN channel gate; cAMP binding relieves this autoinhibition so that opening becomes more favorable thermodynamically. This autoinhibition-relief mechanism is conserved with that of several other cyclic nucleotide receptors using the same ligand-binding fold. Besides its thermodynamic effect, cAMP also modulates the depolarization-dependent deactivation rate by kinetically that is formed by mode shift after prolonged hyperpolarization activation. This hysteretic activation-deactivation cycle is preserved by CSD substitution, but the change in deactivation kinetics of the liganded channel resulting from CSD substitution is not correlated with the change in autoinhibition properties. Thus the liganded and the unliganded forms of the CSD respectively provide the structural determinants for open-state trapping and autoinhibition, such that two distinct mechanisms for cAMP regulation can operate in one receptor. HCN channels are tetramers of homologous subunits; each subunit has six membrane-spanning helices (S1-S6) homologous to those of voltage-gated potassium channels, with a voltagesensing domain in S1-S4 (4). Hyperpolarization drives inward movement of the positively charged S4 (5), which is coupled to opening of the pore gate formed by the cytoplasmic C-terminal ends of the four S6 helices in the tetramer (6). S6 in each subunit is followed by an 80-residue "C-linker" with an unusual multihelix fold (7), then the cAMP-binding fold and a poorly conserved "extreme C-terminal" region. The C-linker and cAMP-binding fold together can be viewed as one "cAMP-sensing domain" (CSD; see Fig. 1A, Top), based on domain stability (7) and the C-linker's functional importance (8).Cyclic AMP binding potentiates hyperpolarization-dependent activation of HCN channels (9). That is, cAMP increases thermodynamic stability of the open channel relative to the closed channel, so that the voltage needed for half-maximal activation (V 1∕2 ) becomes less negative. A similar V 1∕2 shift can be produced by deleting the CSD through enzymatic or genetic truncation (10, 11). This establishes a classical autoinhibition mechanism (12) as the basis for cAMP regulation of HCN channels, in analogy with PKA (13) and EPAC (14). Thus the unliganded ("apo") CSD inhibits an intrinsic activity of the channel, and the liganded ("holo") form of the CSD has weakened or nonexistent capability for this inhibition, so that cAMP binding mimics CSD deletion. Because the autoinhibition-relief model attributes specific regulatory function to the apo CSD rather than the holo CSD, we introduce the designation "apo-driven" for this mechanism type. In a "holo-driven" mechanism, by contrast, the presence of the CSD with bound ligand would be required for a particular HCN channel structure that achieves optimal activation. A holodriven mechanis...

show abstract

mentioning

confidence: 99%

Cytoplasmic cAMP-sensing domain of hyperpolarization-activated cation (HCN) channels uses two structurally distinct mechanisms to regulate voltage gating

Wicks

Wong²,

Sun³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…HCN1 was overexpressed in the guinea pig ventricle, after which sinus node was ablated using radiofrequency energy. Large If current with activation kinetics mimicking sinus node was detected [46]. A different approach has been utilized employing Adenylate Cyclase type VI gene delivered with adenoviruses.…”

Section: Gene-based Approachesmentioning

confidence: 99%

Biological Pacemakers – A Review

Gunasekaran

Selvaraj

2018

ijcp

View full text Add to dashboard Cite

Slow heart rates, due to sinus node disease or atrioventricular conduction block, are a significant problem for many patients. Currently, these patients are treated with electronic pacemakers, which provide effective therapy, but are also associated with many problems. Use of biological pacemakers is an attractive solution to these problems. Approaches for the creation of such pacemakers include either the injection of cells that have pacemaker activity (cell-based approach) or modification of cells in the heart to induce pacemaker activity by delivering genes (gene-based approach). This article reviews the progress in the development of biological pacemakers.

show abstract

“…28,29 Ventricular tachycardia was reproducibly induced in the animals with remodeled hearts. Sick sinus syndrome and complete atrio-ventricular block was created by ablating either the sinus node 30 or the atrio-ventricular node. [31][32][33] These models require pacemaker implantation to compensate for a low escape beat.…”

Section: Ischemic Heart Failure Modelmentioning

confidence: 99%