Sympathetic neurons mediate developmental change in cardiac sodium channel gating through long-term neurotransmitter action.
Innervation of nerve and muscle cells during development is often accompanied by changes in the expression and function of ion channels in the postsynaptic cell. However, the signaling pathways whereby the presynaptic nerve influences the properties of the postsynaptic cell are less well understood. Indirect evidence suggests that cardiac voltage-gated Na+ channels undergo important changes during development. Here, we compare directly single voltage-gated Na+ channel currents from neonatal and adult rat ventricular myocytes and report a negative shift in the voltage dependence of channel gating during development, leading to a significant speeding of channel activation and inactivation at a fixed membrane potential. These developmental changes can be mimicked in vitro by innervation of neonatal myocytes with sympathetic neurons. The effect of sympathetic neurons is blocked by the beta-adrenergic receptor antagonist propranolol and is mimicked by prolonged coculture of neonatal myocytes with a membrane-permeable cAMP analog. Thus presynaptic neurons can control the developmental phenotype of ion channels in a postsynaptic cell through a classic receptor-mediated neurotransmitter action that involves a defined second messenger pathway.
Department of Pharmacology, Columbia University, New York, New York 10032.
J F
JF
Zhang
R B
RB
Robinson
S A
SA
Siegelbaum
D000320:Adrenergic Fibers / Q000502:physiology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology; D004558:Electric Stimulation; D006321:Heart / Q000502:physiology*; D015640:Ion Channel Gating / Q000502:physiology*; D008564:Membrane Potentials / Q000502:physiology; D009206:Myocardium / Q000166:cytology* / Q000648:ultrastructure; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology; D015290:Second Messenger Systems / Q000502:physiology; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
D000319:Adrenergic beta-Antagonists; D018377:Neurotransmitter Agents; D011943:Receptors, Adrenergic, beta; D015222:Sodium Channels; D011433:Propranolol; D000242:Cyclic AMP