Mechanism of α-adrenergic regulation of expressed hKv4.3 currents

Sunny S. Po, Richard C. Wu, George J. Juang, Wei Kong, Gordon F. Tomaselli

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

The transient outward potassium current (Ito) is an important repolarizing current in the mammalian heart. Ito is regulated by adrenergic stimulation; however, the effect of agonists on this current, and consequently the action potential duration and profile, is variable. An important source of the variability is the difference in the channel genes that underlie Ito. There are two subfamilies of candidate genes that are likely to encode Ito in the mammalian heart: Kv4 and Kv1.4; the predominance of either gene is a function of the species, stage of development, and region of the heart. The existence of different isoforms of the Kv4 family (principally Kv4.2 or Kv4.3) further complicates the effect of α-adrenergic modulation of cardiac Ito. In the human ventricle, hKv4.3 is the predominant gene underlying Ito. Two splice variants of human Kv4.3 (hKv4.3) are present in the human ventricle; the longer splice variant contains a 19-amino acid insert in the COOH-terminus with a consensus protein kinase C (PKC) site. We used heterologous expression of hKv4.3 splice variants and studies of human ventricular myocytes to demonstrate that α-adrenergic modulation of Ito occurs through a PKC signaling pathway and that only the long splice variant (hKv4.3-L) is modulated via this pathway. Only a single hKv4.3-L monomer in the tetrameric Ito channel is required to confer sensitivity to phenylephrine (PE). Mutation of the PKC site in hKv4.3-L eliminates α-adrenergic modulation of the hKv4.3-encoded current. The similar, albeit less robust, modulation of human ventricular Ito by PE suggests that hKv4.3-L is expressed in a functional form in the human heart.

Original languageEnglish (US)
JournalAmerican Journal of Physiology
Volume281
Issue number6 PART 2
StatePublished - Dec 2001

Fingerprint

Adrenergic Agents
Protein Kinase C
Phenylephrine
Genes
Muscle Cells
Action Potentials
Potassium
Protein Isoforms
Amino Acids
Mutation

Keywords

  • Adrenergic receptors
  • Heterologous expression
  • Phorbol esters
  • Potassium channels
  • Protein kinase C
  • Site-directed mutagenesis

ASJC Scopus subject areas

  • Physiology (medical)

Cite this

Po, S. S., Wu, R. C., Juang, G. J., Kong, W., & Tomaselli, G. F. (2001). Mechanism of α-adrenergic regulation of expressed hKv4.3 currents. American Journal of Physiology, 281(6 PART 2).

Mechanism of α-adrenergic regulation of expressed hKv4.3 currents. / Po, Sunny S.; Wu, Richard C.; Juang, George J.; Kong, Wei; Tomaselli, Gordon F.

In: American Journal of Physiology, Vol. 281, No. 6 PART 2, 12.2001.

Research output: Contribution to journalArticle

Po, SS, Wu, RC, Juang, GJ, Kong, W & Tomaselli, GF 2001, 'Mechanism of α-adrenergic regulation of expressed hKv4.3 currents', American Journal of Physiology, vol. 281, no. 6 PART 2.
Po, Sunny S. ; Wu, Richard C. ; Juang, George J. ; Kong, Wei ; Tomaselli, Gordon F. / Mechanism of α-adrenergic regulation of expressed hKv4.3 currents. In: American Journal of Physiology. 2001 ; Vol. 281, No. 6 PART 2.
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abstract = "The transient outward potassium current (Ito) is an important repolarizing current in the mammalian heart. Ito is regulated by adrenergic stimulation; however, the effect of agonists on this current, and consequently the action potential duration and profile, is variable. An important source of the variability is the difference in the channel genes that underlie Ito. There are two subfamilies of candidate genes that are likely to encode Ito in the mammalian heart: Kv4 and Kv1.4; the predominance of either gene is a function of the species, stage of development, and region of the heart. The existence of different isoforms of the Kv4 family (principally Kv4.2 or Kv4.3) further complicates the effect of α-adrenergic modulation of cardiac Ito. In the human ventricle, hKv4.3 is the predominant gene underlying Ito. Two splice variants of human Kv4.3 (hKv4.3) are present in the human ventricle; the longer splice variant contains a 19-amino acid insert in the COOH-terminus with a consensus protein kinase C (PKC) site. We used heterologous expression of hKv4.3 splice variants and studies of human ventricular myocytes to demonstrate that α-adrenergic modulation of Ito occurs through a PKC signaling pathway and that only the long splice variant (hKv4.3-L) is modulated via this pathway. Only a single hKv4.3-L monomer in the tetrameric Ito channel is required to confer sensitivity to phenylephrine (PE). Mutation of the PKC site in hKv4.3-L eliminates α-adrenergic modulation of the hKv4.3-encoded current. The similar, albeit less robust, modulation of human ventricular Ito by PE suggests that hKv4.3-L is expressed in a functional form in the human heart.",
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AB - The transient outward potassium current (Ito) is an important repolarizing current in the mammalian heart. Ito is regulated by adrenergic stimulation; however, the effect of agonists on this current, and consequently the action potential duration and profile, is variable. An important source of the variability is the difference in the channel genes that underlie Ito. There are two subfamilies of candidate genes that are likely to encode Ito in the mammalian heart: Kv4 and Kv1.4; the predominance of either gene is a function of the species, stage of development, and region of the heart. The existence of different isoforms of the Kv4 family (principally Kv4.2 or Kv4.3) further complicates the effect of α-adrenergic modulation of cardiac Ito. In the human ventricle, hKv4.3 is the predominant gene underlying Ito. Two splice variants of human Kv4.3 (hKv4.3) are present in the human ventricle; the longer splice variant contains a 19-amino acid insert in the COOH-terminus with a consensus protein kinase C (PKC) site. We used heterologous expression of hKv4.3 splice variants and studies of human ventricular myocytes to demonstrate that α-adrenergic modulation of Ito occurs through a PKC signaling pathway and that only the long splice variant (hKv4.3-L) is modulated via this pathway. Only a single hKv4.3-L monomer in the tetrameric Ito channel is required to confer sensitivity to phenylephrine (PE). Mutation of the PKC site in hKv4.3-L eliminates α-adrenergic modulation of the hKv4.3-encoded current. The similar, albeit less robust, modulation of human ventricular Ito by PE suggests that hKv4.3-L is expressed in a functional form in the human heart.

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