The mechanisms underlying cardiac automaticity are still incompletely
understood and controversial. Here we report the complete conditional and
time-controlled silencing of the "funny" current
(If) by expression of a dominant-negative,
non-conductive HCN4-channel subunit (hHCN4-AYA). Heart-specific
If silencing caused altered
[Ca2+]i release and Ca2+ handling in the
sinoatrial node, impaired pacemaker activity, and symptoms reminiscent of severe
human disease of pacemaking. The effects of If
silencing critically depended on the activity of the autonomic nervous system.
We were able to rescue the failure of impulse generation and conduction by
additional genetic deletion of cardiac muscarinic G-protein-activated (GIRK4)
channels in If-deficient mice without impairing
heartbeat regulation. Our study establishes the role of f-channels in cardiac
automaticity and indicates that arrhythmia related to HCN
loss-of-function may be managed by pharmacological or genetic inhibition of
GIRK4 channels, thus offering a new therapeutic strategy for the treatment of
heart rhythm diseases.
In vivo axon pathfinding mechanisms in the neuron-dense brain remain relatively poorly characterized. We study the Drosophila mushroom body (MB) axons, whose α and β branches connect to different brain areas. We show that the Ryk family WNT5 receptor, DRL (derailed), which is expressed in the dorsomedial lineages, brain structure precursors adjacent to the MBs, is required for MB α branch axon guidance. DRL acts to capture and present WNT5 to MB axons rather than transduce a WNT5 signal. DRL's ectodomain must be cleaved and shed to guide α axons. DRL-2, another Ryk, is expressed within MB axons and functions as a repulsive WNT5 signaling receptor. Finally, our biochemical data support the existence of a ternary complex composed of the cleaved DRL ectodomain, WNT5, and DRL-2. Thus, the interaction of MB-extrinsic and -intrinsic Ryks via their common ligand acts to guide MB α axons.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.