PDE type-4 inhibition increases L-type Ca2+ currents, action potential firing, and quantal size of exocytosis in mouse chromaffin cells

A. Marcantoni, V. Carabelli, D. H. Vandael, V. Comunanza, E. Carbone

Research output: Contribution to journalArticle

Abstract

We studied the effects of the cAMP-hydrolyzing enzyme phosphodiesterase type-4 (PDE4) on the L-type Ca2+ channels (LTCCs) and Ca 2+-dependent secretion in mouse chromaffin cells (MCCs). The selective PDE4 inhibitor rolipram (3 μM) had a specific potentiating action on Ca2+ currents of MCCs (40% increase within 3 min). A similar effect was produced by the selective β1-AR agonist denopamine (1 μM) and by the unselective PDEs inhibitor IBMX (100 μM). Rolipram and denopamine actions were selective for LTCCs, and the Ca2+ current increase remained unchanged if the two compounds were applied simultaneously. This suggests that at rest, LTCCs in MCCs are down-regulated by the low levels of cAMP determined by PDE4 activity and that LTCCs can be up-regulated by either inhibiting PDE4 or activating β1-AR. No other PDEs are likely involved in this specific action. PDE4 inhibition had also a marked effect on the spontaneous firing of resting MCCs and catecholamine secretion. Rolipram up-regulated the LTCCs contributing to the "pace-maker" current underlying action potential (AP) discharges and accelerated the firing rate, with no significant effects on AP waveform. Acceleration of AP firing was also induced by the LTCC-agonist Bay K (1 μM), while nifedipine (3 μM) reduced the firing frequency, suggesting that LTCCs and intracellular cAMP play a key role in setting the pace-maker current regulating MCCs excitability. Rolipram increased also the size of the ready-releasable pool and the quantal content of secretory vesicles without affecting their probability of release. Thus, rolipram acts on MCCs by up-regulating both exocytosis and AP firings. These two processes are effectively down-regulated by PDE4 at rest and can dramatically increase the quantity of released catecholamines when PDE4 is inhibited and/or cAMP is raised.

Original languageEnglish
Pages (from-to)1093-1110
Number of pages18
JournalPflugers Archiv European Journal of Physiology
Volume457
Issue number5
DOIs
Publication statusPublished - Mar 2009

Keywords

  • Amperometry
  • Calcium channel
  • cAMP
  • Capacitance
  • Chromaffin cells

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Physiology (medical)

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