Sodium Leak Current through a Non-selective Cation Channel Regulates Spontaneous Activity of Pacemaker Cells

Pacemaker cells are involved in regulating numerous essential biological functions. These cells exhibit spontaneous activities in isolation, due to the various membrane ion channels. Background conductances (ILeak) are responsible for the depolarized resting membrane potential of numerous pacemaker cells, largely due to a high sodium component (INa Leak); however, their molecular identity remains unclear. NALCN is a non-selective cationic channel that was suggested as a major contributor to the background Na + conductance in some neurons. This thesis investigates whether and how NALCN contributes to the INa Leak of two major pacemaker systems: neurons and heart. Chapter 4 utilizes the benefits of a simplified respiratory pacemaker neuron of L. stagnalis to determine whether NALCN has a functional role in regulating pacemaker cell activity and function. Using an acute gene silencing approach, reduction of endogenous NALCN orthologue expression in isolated respiratory pacemaker neuron hyperpolarized the resting membrane potential, due largely to the reduction of INa Leak, which partially affect respiratory behavioural output. Chapter 5 further determined that the NALCN orthologue of is a major contributing current to the pacemaker neuron subthreshold conductance. By using a computation model, developed in collaboration, simulation of spontaneous pacemaker activity was shown to be more sensitive to Na + leak than K + leak conductance. Together, these