Activation of protein kinase C potentiates norepinephrine release from sinus node

Area of Science:

• Cardiovascular Physiology
• Neuropharmacology
• Cell Signaling

Background:

• Norepinephrine (NE) release from sympathetic nerve terminals is crucial for regulating heart rate.
• The role of protein kinase C (PKC) in modulating neurotransmitter release at the cardiac synapse is not fully understood.
• Specific binding sites for phorbol esters, activators of PKC, exist in cardiac tissue.

Purpose of the Study:

• To investigate the localization of [20-3H]phorbol-12,13-dibutyrate ([3H]PDBu) binding sites in the guinea pig heart.
• To determine the involvement of Ca2+-phospholipid-dependent protein kinase (protein kinase C) in norepinephrine release from guinea pig sinus node sympathetic nerve terminals.

Main Methods:

• Localization of specific [3H]PDBu binding sites in the guinea pig heart.
• Measurement of [3H]NE release evoked by electrical stimulation or Ca2+ ionophore in guinea pig sinus node preparations.
• Assessment of the effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) and protein kinase C inhibitors (polymyxin B, H-7) on [3H]NE release.

Main Results:

• A single class of specific [3H]PDBu binding sites was identified in the heart.
• TPA potentiated the evoked release of [3H]NE from the sinus node.
• The potentiating effect of TPA was blocked by protein kinase C inhibitors, polymyxin B and H-7.
• TPA increased the apparent affinities for extracellular Ca2+ in electrical stimulation-evoked release.

Conclusions:

• Protein kinase C is involved in the release of norepinephrine from sympathetic nerve terminals in the guinea pig sinus node.
• PKC activation may modulate transmembrane signal transduction pathways regulating NE release.
• Further research is warranted to elucidate the precise role of PKC in adrenergic neurotransmission in the heart.