Title

Inhibition of Adenylate Cyclase Attenuates Muscarinic Ca2+ Signaling by a PKA-Independent Mechanism in Rat Carotid Body Type I Cells

Document Type

Article

Publication Date

1-31-2011

Abstract

Carotid body (CB) Type I cells respond to hypoxia by releasing excitatory and inhibitory neurotransmitters. This mechanism leads to increased firing of the carotid sinus nerve (CSN) which alters breathing to maintain blood gases within the physiological range. Acetylcholine targets both muscarinic and nicotinic receptors in the rat CB, acting postsynaptically on CSN and presynaptically on Type I cells. Muscarinic Ca2+ signaling is inhibited by the activation of Gi-coupled receptors including histamine H3 receptors. Here inhibition of adenylate cyclase with SQ22536 mimicked H3 receptor activation. Using Ca2+ imaging techniques it was observed that inhibition of muscarinic Ca2+ signaling was independent of protein kinase A (PKA) as PKA inhibitors H89 and KT5720 were without effect on the muscarinic Ca2+ response. By contrast the Epac (exchange protein activated by cAMP) inhibitor brefeldin A inhibited muscarinic Ca2+ signaling whereas the Epac activator 8-pCPT-2′-O-Me-cAMP-AM potentiated Ca2+ signaling.

Thus in Type I cells inhibition of adenylate cyclase inhibited muscarinic Ca2+ signaling via a PKA-independent pathway that may rely upon modulation of Epac.

DOI

10.1016/j.resp.2010.09.013