Effect of the gating pore blocker 1-(2,4-xylyl)guanidinium on the firing rate of isolated mouse sinus node cells

Among excitable cells, a small subset are able to spontaneously generate action potentials at a steady frequency. These are known as pacemaker cells. They can be divided into two distinct categories based on their firing frequency : fast pacemakers (>10 Hz) and slow pacemakers (<10 Hz). While some mechanisms for fast pacemaking are known (e.g. presence of a so-called resurgent current from voltage-gated sodium channels (Nav)), the mechanism underlying slow pacemaking is still unclear, for example in sinus node cells of the heart. The main hypothesis is that an inward current below 10 pA is needed to generate a steady slow activity. This current can either be the result of cooperativity between conventional ion channels or a a high expression of channels with a small unitary conductance. We tested the latter hypothesis in midbrain dopamine (DA) neurons using the gating-pore blocker 1-(2,4-xylyl)guanidinium (XG) and found out that this agent completely blocked pacemaking in these neurons (Jehasse et al. 2021), although the target of XG in these cells remains unknown. Because DA neurons and sino-atrial node (SAN) cells share many electrophysiological features, we examined the effect of XG in SAN cells, using voltage and current clamp configuration of the patch clamp technique.​