Cardiac Nicotinic Receptors Show Beta-Subunit-Dependent Compensatory Changes

Nicotinic receptors (NRs) play an important role in the cholinergic regulation of heart functions, and converging evidence suggests a diverse repertoire of NR subunits in the heart. A recent hypothesis about the plasticity of beta NR subunits suggests that beta 2-subunits and beta 4-subunits may substitute for each other. In our study, we assessed the hypothetical beta-subunit interchangeabil- ity in the heart at the level of mRNA. Using two mutant mice strains lacking beta 2 or beta 4 NR subunits, we examined the relative expression of NR subunits and other key cholinergic molecules. We investigated the physiology of isolated hearts perfused by Langendorffs method at basal conditions and after cholinergic and/or adrenergic stimulation. Lack of beta 2 NR subunit was accompanied with decreased relative expression of beta 4-subunits and alpha 3-subunits. No other cholinergic changes were observed at the level of mRNA, except for increased M3 and decreased M4 muscarinic receptors. Isolated hearts lacking beta 2 NR subunit showed different dynamics in heart rate response to indirect cholinergic stimulation. In hearts lacking beta 4 NR subunit, increased levels of beta 2-subunits were observed together with decreased mRNA for acetylcholine-synthetizing enzyme and M1 and M4 muscarinic receptors. Changes in the expression levels in beta 4(-/-) hearts were associated with increased basal heart rate and impaired response to a high dose of acetylcholine upon adrenergic stimulation. In support of the proposed plasticity of cardiac NRs, our results confirmed subunit-dependent compensatory changes to missing cardiac NRs subunits with consequences on isolated heart physiology.NEW & NOTEWORTHY In the present study, we observed an increase in mRNA levels of the beta 2 NR subunit in beta 4(-/-) hearts but not vice versa, thus supporting the hypothesis of beta NR subunit plasticity that depends on the specific type of missing beta-subunit. This was accompanied with specific cholinergic adaptations. Nevertheless, isolated hearts of beta 4(-/-) mice showed increased basal heart rate and a higher sensitivity to a high dose of acetylcholine upon adrenergic stimulation.