The current opinion manuscript posits that not only Piezo2 voltage block, but also
proton affinity and availability in relation to Piezo2, a mechanically gated ion channel,
may count in the mediation of pain and its sensitivity. Moreover, this paper argues
that autonomously acquired Piezo2 channelopathy on somatosensory terminals is likely
the initiating peripheral impaired input source that drives the central sensitization
of spinal nociceptive neurons on the chronic path as being the autonomous pain generator.
In parallel, impaired proprioception and the resultant progressive deficit in neuromuscular
junctions of motoneurons might be initiated on the chronic path by the impairment
of the proton-based ultrafast proprioceptive feedback to motoneurons due to disconnection
through vesicular glutamate transporter 1. The irreversible form of this autonomously
acquired Piezo2 ion channel microdamage, in association with genetic predisposition
and/or environmental risk factors, is suggested to lead to progressive motoneuron
death in addition to loss of pain sensation in amyotrophic lateral sclerosis. Furthermore,
the impairment of the proton-based ultrafast long-range oscillatory synchronization
to the hippocampus through vesicular glutamate transporter 2 may gain further importance
in pain modulation and formation on the chronic path. Overall, this novel, unaccounted
Piezo2-initiated protonic extrafast signaling, including both the protonic ultrafast
proprioceptive and the rapid nociceptive ones, within the nervous system seems to
be essential in order to maintain life. Hence, its microdamage promotes neurodegeneration
and accelerates aging, while the complete loss of it is incompatible with life sustainment,
as is proposed in amyotrophic lateral sclerosis.
