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Defective "pacemaker" current (Ih) in a zebrafish mutant with a slow heart rate
K Baker1, K S Warren, G Yellen
1Department of Neurobiology, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114, USA.
Summary
The zebrafish mutation slow mo reduces heart rate by diminishing the hyperpolarization-activated inward current (Ih). This finding strongly suggests Ih is crucial for the heart's natural pacemaking function in vivo.
Area of Science:
- Cardiovascular Physiology
- Molecular Biology
- Zebrafish Genetics
Background:
- Cardiac pacemaking, essential for heart rate and rhythm, relies on slow membrane depolarization between action potentials.
- The specific ionic currents responsible for this pacemaker potential and their in vivo roles remain debated.
Purpose of the Study:
- To investigate the in vivo role of ionic currents in cardiac pacemaking.
- To correlate cellular ionic currents with the rhythmic properties of the intact heart using a zebrafish model.
Main Methods:
- Utilized the zebrafish Danio rerio and its recessive mutation slow mo (smo), which causes a reduced embryonic heart rate.
- Developed methods for culturing zebrafish embryonic cardiocytes for cellular analysis.
- Performed patch-clamp analysis on cultured cardiocytes to assess ionic currents.
Main Results:
- Zebrafish embryos with the smo mutation exhibited a quantifiable reduction in heart rate.
- Cultured cardiocytes from smo mutants maintained a slower beating rate.
- Patch-clamp analysis revealed normal expression of sodium, calcium (T-type, L-type), and potassium currents.
- A significant reduction in the hyperpolarization-activated inward current (Ih) was observed in smo cardiomyocytes, specifically affecting one kinetic component.
Conclusions:
- The hyperpolarization-activated inward current (Ih) is a critical contributor to cardiac pacemaking.
- The smo mutation provides strong evidence for the essential role of Ih in regulating the heart's intrinsic rhythm.