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Negative modulation of L-type Ca2+ channels via beta-adrenoceptor stimulation in guinea-pig detrusor smooth muscle

Hiroyuki Kobayashi1, Takashi Miwa, Taku Nagao

  • 1Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi, Fukuoka 812-8582, Japan.

European Journal of Pharmacology
|June 6, 2003
PubMed

Insights

Beta-adrenergic stimulation inhibits L-type Ca(2+) channels in guinea-pig detrusor smooth muscle. This effect is mediated by cyclic adenosine monophosphate (cAMP) and protein kinase A, clarifying a previously controversial mechanism.

Area of Science:

  • Pharmacology
  • Physiology
  • Molecular Biology

Background:

  • Beta-adrenergic stimulation's effect on L-type Ca(2+) channels is well-established in cardiac cells but controversial in smooth muscle.
  • The precise mechanism of beta-adrenergic modulation of L-type Ca(2+) channels in smooth muscle remains unclear.

Purpose of the Study:

  • To investigate the effect of beta-adrenergic stimulation on L-type Ca(2+) channel activity in guinea-pig detrusor smooth muscle.
  • To elucidate the underlying molecular mechanisms involved in this modulation.

Main Methods:

  • Electrophysiological recordings of barium currents (I(Ba)) through L-type Ca(2+) channels.
  • Application of isoproterenol, forskolin, 8-bromoadenosine 3'5'-cyclic monophosphate (8-Br-cAMP), and intracellular cAMP.
  • Inhibition of protein kinase A.

Main Results:

  • Isoproterenol (0.1-1 microM) significantly inhibited Ba(2+) currents (I(Ba)) through L-type Ca(2+) channels.
  • Isoproterenol shifted the steady-state inactivation curve negatively by 11 mV without altering activation curves.
  • Forskolin, 8-Br-cAMP, and intracellular cAMP mimicked isoproterenol's inhibitory effects, which were reversed by protein kinase A inhibition.

Conclusions:

  • Beta-adrenergic stimulation negatively modulates L-type Ca(2+) channels in detrusor smooth muscle.
  • This modulation is dependent on the cyclic adenosine monophosphate (cAMP)/protein kinase A signaling pathway.

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