Other inward currents that help generate intrinsic spiking and bursting in pacemaker neurons are the calcium current and calcium-activated nonspecific currents (ICAN). When a neuron becomes depolarized, voltage gated calcium channels become activated and calcium is able to flow into the cell which usually leads to the release of neurotransmitters. Calcium-sensitive dyes have shown that internal concentrations of calcium increase during bursts. The activation of different calcium channels has distinct effects on the activity of neurons in the pre-Bötzinger complex. L-type calcium channels are known to increase the frequency of action potentials in some neurons, which might be the reason calcium influx through these channels has been observed during the augmentation when tissues have low levels of oxygen. P/Q-type calcium channels are mainly responsible for the release of neurotransmitters that excite, or activate, postsynaptic neurons. Studies have shown that blockage of these channels leads to the inhibition of sighs, which indicates calcium flow through these channels is necessary for sighs. Other research has also suggested that calcium flow through N-type calcium channels is essential for normal breathing, and is responsible for the activation of calcium-dependent potassium channels. Calcium-activated nonselective cation currents are important for the intrinsic spiking and bursting activity in CS pacemaker neurons. Metabotropic glutamate 1/5 receptors appear to be important for the increase in intracellular calcium that activate ICAN. The initial burst in a neuron usually leads to the activation of the transient sodium current and the several types of calcium currents.These currents depolarize the cell further enough to activate NMDA receptors and ICAN, which helps cell regenerate its bursts.