Functional and molecular evidence of MaxiK channel beta1 subunit decrease with coronary artery ageing in the rat

J Physiol. 2004 Sep 15;559(Pt 3):849-62. doi: 10.1113/jphysiol.2004.068676. Epub 2004 Jul 22.

Abstract

Large-conductance, voltage- and Ca2+ -activated K+ channels (MaxiK, BK) are key regulators of vascular tone. Vascular MaxiK are formed by the pore-forming alpha subunit and the modulatory beta1 subunit, which imprints unique kinetics, Ca2+/voltage sensitivities and pharmacology to the channel. As age progresses, alpha subunit functional expression and protein levels diminish in coronary myocytes. However, whether ageing modifies beta1 subunit expression or the mechanism of alpha subunit reduction is unknown. Thus, we examined functional and pharmacological characteristics of MaxiK, as well as alpha and beta1 transcript levels in coronary myocytes from young and old F344 rats. The mechanism of age-dependent alpha subunit protein reduction involves its transcript downregulation. A corresponding loss of beta1 transcripts was also detected in old myocytes, suggesting a proportional age-dependent decrease of beta1 to alpha subunit protein. Indeed, MaxiK channel properties, defined by coassembly of beta1 and alpha subunits, were equivalent in young versus old, for example in terms of (i) activation kinetics, (ii) sensitivity to Ca2+ levels > 1 microm (iii) dehydrosoyasaponin-I-induced activation, and (iv) iberiotoxin blockade. Consistent with less MaxiK expression/function in older myocytes, the ability of iberiotoxin to contract coronary rings was reduced approximately 50% with ageing confirming our previous findings. 5-Hydroxytryptamine (5-HT) contractile efficacy was reduced by iberiotoxin pretreatment in young > old coronary arteries (explained by larger iberiotoxin-induced contraction and decreased dynamic range for 5-HT contraction in young versus old) with no apparent differences in nitroglycerine-induced relaxation. We propose that the age-related MaxiK reduction involves a parallel decrease of alpha and beta1 functional expression via a transcript downregulatory mechanism; a major impact on basal and possibly stimulated coronary contraction may contribute to altered coronary flow regulation and coronary morbidity in the elderly.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aging / drug effects
  • Aging / physiology*
  • Animals
  • Coronary Vessels / drug effects
  • Coronary Vessels / physiology*
  • Dose-Response Relationship, Drug
  • In Vitro Techniques
  • Large-Conductance Calcium-Activated Potassium Channel alpha Subunits
  • Large-Conductance Calcium-Activated Potassium Channels
  • Male
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Potassium Channel Blockers / pharmacology
  • Potassium Channels, Calcium-Activated / antagonists & inhibitors
  • Potassium Channels, Calcium-Activated / physiology*
  • Rats
  • Rats, Inbred F344

Substances

  • Kcnma1 protein, rat
  • Large-Conductance Calcium-Activated Potassium Channel alpha Subunits
  • Large-Conductance Calcium-Activated Potassium Channels
  • Potassium Channel Blockers
  • Potassium Channels, Calcium-Activated