Lu AE98134 is a Selective Positive Modulator of NaV1.1 Channels

Sodium channels are integral membrane proteins that form ion channels and conduct sodium ions (Na+) through the plasma membrane. These channels pass through three different states, which are resting state, active state, and inactive state. Specifically, sodium channel proteins are Nav1.1 to Nav1.9.

The lack of fast synaptic central neurons (FSIN) that express calcium-binding albumin and parvalbumin (PAV) is the cause of schizophrenia. Besides, FSIN can release the inhibitory neurotransmitter GABA at a high rate, thus synchronously releasing the main neurons from the cortex. Moreover, the recovery of FSIN in PFC can effectively alleviate the symptoms of schizophrenia. FSIN expressed the Nav1.1 channel in its axonal initiation ganglion. Nav1.1 channel is essential to maintain sustained rapid spike. Moreover, the selective activation of the Nav1.1 channel can regulate the emission mode of FSIN. Today, we will introduce a potent and partly selective positive modulator of NaV1.1 channels, Lu AE98134.

Lu AE98134 is a potent and partly selective positive modulator of NaV1.1 channels.

At first, Lu AE98134 is a potent activator of NaV1.1 channels. Lu AE98134 also increases the activity of Nav1.2 and Nav1.5 channels but not of Nav1.4, Nav1.6 and Nav1.7 channels. Meanwhile, Lu AE98134 can be used to analyze pathophysiological functions of the Nav1.1 channel in various central nervous system diseases. Nonetheless, They include cognitive restoring in schizophrenia, et al.

Secondly, Lu AE98134 (30 μM) promotes the current mediated by the NaV1.1 channel. Interestingly, it activates NaV1.1 and NaV1.5 and to a lesser extent NaV1.2. Importantly, Lu AE98134 has no effect on NaV1.4, NaV1.6 and NaV1.7 currents in HEK cells expressing NaV1.1, NaV1.2, NaV1.6, NaV1.5, NaV1.6, and NaV1.7. Particularly, Lu AE98134 (30 μM) increases the excitability of FSINs by decreasing the threshold for action potentials. Additionally, Lu AE98134 increases the excitability since each current pulse generated a higher number of spikes.

Thirdly, Lu AE98134 (30 μM) increases the excitability of FSINs neurons from normal and Dlx5/6+/− animals by modulating several parameters characteristic for NaV1.1 channels. Obviously, the selective activation of FSINs by Lu AE98134 restores cognitive flexibility in adult Dlx5/6+/− mice.

All in all, Lu AE98134 is a potent and partly selective positive modulator of NaV1.1 channels.

References:

 Nadia Lybøl von Schoubye, et al. Neurosci Lett. 2018 Jan 1;662:29-35.