**1. Introduction**

Touch, proprioception, and nociception are the fundamental senses mediated by activation of mechanosensitive ion channels, which are expressed in various types of sensory neurons. The detection of mechanical forces is mediated by different ion channels such as mechanosensitive ion channels (MSCs), potassium K2P channels, TMEM63/OSCA, and TMC1/2 [1]. In the current review, we will focus on the potential role of the recently discovered mechanosensitive Piezo1/2 channels in the nociceptive signaling in migraine. Migraine pain remains poorly understood mainly because of lack of mechanistic explanations for the initial steps in generation of pain signals in the nociceptive system.

Migraine, a very common neurological disorder, is characterized by severe and long-lasting headache associated also with mechanical hypersensitivity and allodynia (pain induced by normally non-painful touch, which, during long-lasting migraine attack, is not limited to the head) [2]. Mechanosensitive ion channels most likely mediate mechanical hypersensitivity in the peripheral or central parts of the nociceptive system. However, nature of these ion channels remains unknown. Therefore, mechanosensitive Piezo channels, recently detected in human trigeminal ganglia [3,4], are the most probable candidates to mediate typical symptoms of migraine, such as mechanical hypersensitivity and pulsating type of migraine pain [5].

## **2. Complex Structure of Gigantic Piezo Channels**

Piezo channels are the family of mechanotransducers composed by two nonselective cationic channels known as Piezo1 and Piezo2 with a relatively homologous structure (Figure 1) [6–9]. Piezo channels are 2500 amino acids long proteins with up to 38 transmembrane segments per monomer. These monomers, combined together, build up the functional homo-trimers in the cell membrane [10]. Notably, these channels do not share sequence or structural homology with other above-mentioned mechanosensitive channels. This makes Piezo channels to be a completely new molecular target for therapeutic interventions, with their own profile of preferential physical triggers, chemical agonists, and specific modulators [11].

The molecule of Piezo1 channel is organized as a gigantic 'three peripheral blade-like structure' (Figure 1A), three 90-Å-long intracellular beam–resembling components bridging the blades together [10]. The central pore, formed by the C-terminals, has a main role in determining the channel conductance and ion selectivity [10]. The intracellular beam, part of the central cap, seems to be the perfect intermediate structure for mechanical transduction from the periphery to the central ion-conducting pore [7].

The uncommon structure of Piezo channels suggests their unique role in mechanical transduction [11], including various important functions in sensory neurons [12].

**Figure 1.** Schematic presentation of the Piezo channel. (**A**) Bird view of the Piezo channel with peripheral blade-like structures located in three subunits forming the trimeric functional unit with the central pore, blades and anchor regions. (**B**) Side view of the Piezo channel located in the lipid cell membrane. The following elements of the single subunit are presented: the intracellular beams, the C-terminals with the anchor regions and the ATM region containing the Yoda1 binding site and the extracellular blades.
