Exposure to cAMP and β‐adrenergic stimulation recruits CaV3 T‐type channels in rat chromaffin cells through Epac cAMP‐receptor proteins

T‐type channels are expressed weakly or not at all in adult rat chromaffin cells (RCCs) and there is contrasting evidence as to whether they play a functional role in catecholamine secretion. Here we show that 3–5 days after application of pCPT‐cAMP, most RCCs grown in serum‐free medium expressed a high density of low‐voltage‐activated T‐type channels without altering the expression and characteristics of high‐voltage‐activated channels. The density of cAMP‐recruited T‐type channels increased with time and displayed the typical biophysical and pharmacological properties of low‐voltage‐activated Ca2+ channels: (1) steep voltage‐dependent activation from −50 mV in 10 mm Ca2+, (2) slow deactivation but fast and complete inactivation, (3) full inactivation following short conditioning prepulses to −30 mV, (4) effective block of Ca2+ influx with 50 μm Ni2+, (5) comparable permeability to Ca2+ and Ba2+, and (6) insensitivity to common Ca2+ channel antagonists. The action of exogenous pCPT‐cAMP (200 μm) was prevented by the protein synthesis inhibitor anisomycin and mimicked in most cells by exposure to forskolin and 1‐methyl‐3‐isobutylxanthine (IBMX) or isoprenaline. The protein kinase A (PKA) inhibitor H89 (0.3 μm) and the competitive antagonist of cAMP binding to PKA, Rp‐cAMPS, had weak or no effect on the action of pCPT‐cAMP. In line with this, the selective Epac agonist 8CPT‐2Me‐cAMP nicely mimicked the action of pCPT‐cAMP and isoprenaline, suggesting the existence of a dominant Epac‐dependent recruitment of T‐type channels in RCCs that may originate from the activation of β‐adrenoceptors. Stimulation of β‐adrenoceptors occurs autocrinally in RCCs and thus, the neosynthesis of low‐voltage‐activated channels may represent a new form of ‘chromaffin cell plasticity’, which contributes, by lowering the threshold of action potential firing, to increasing cell excitability and secretory activity during sustained sympathetic stimulation and/or increased catecholamine circulation.