Cinnamaldehyde interacts with the local anesthetic pocket of the Na _V 1.5 channel

Cinnamaldehyde (CA) is extensively used as flavorant and in traditional medicine. CA is commonly used in pain research as specific agonist of TRPA1, a polymodal cation channel expressed in nociceptive primary sensory neurons. However, we previously showed that CA inhibits the L-type Ca ²⁺ channel in cardiac and smooth muscle cells, raising the possibility that other ion channels can be modulated by this compound as well. Here, we investigated whether CA exhibits affects the activity on the cardiac Na _V 1.5 channel. We used the whole-cell patch-clamp technique to record Na ⁺ currents in HEK293T cells expressing the human Na _V 1.5 channel, as well as in cells expressing hNa _V 1.5 channels baring mutation in the binding pocket of local anesthetics (LA). Our results show that CA exhibit LA-like actions on hNa _V 1.5 channels: CA blocks hNa _V 1.5 currents in a tonic and voltage-dependent fashion. Residues F1760 and Y1767 are important for the blockade of Na _V 1.5 by CA and a double point mutation F1760A/Y1767A abolishes the blockade of I _Na by CA. We conclude that CA inhibits the cardiac Na _V 1.5 channel by interacting with the LID binding site and that CA has LA-like actions.