Distinct Modes of Presynaptic Inhibition of Cutaneous Afferents and Their Functions in Behavior

Zimmerman, Amanda; Kovatsis, Eleni M.; Pozsgai, Riana Y.; Tasnim, Aniqa; Zhang, Qiyu; Ginty, David D.

doi:10.1016/j.neuron.2019.02.002

Cited by 60 publications

(104 citation statements)

References 61 publications

(67 reference statements)

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“…The integration of sensory modalities occurs within the CNS and results in cognitive awareness of our surroundings (49)(50)(51)(52). The work reported here shows that, in addition to this central integration, thermal and mechanical stimuli begin to interact at the level of cutaneous mechanoreceptors.…”

Section: Discussionmentioning

confidence: 68%

Piezo2 integrates mechanical and thermal cues in vertebrate mechanoreceptors

Wang

Nikolaev

Gracheva

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Tactile information is detected by thermoreceptors and mechanoreceptors in the skin and integrated by the central nervous system to produce the perception of somatosensation. Here we investigate the mechanism by which thermal and mechanical stimuli begin to interact and report that it is achieved by the mechanotransduction apparatus in cutaneous mechanoreceptors. We show that moderate cold potentiates the conversion of mechanical force into excitatory current in all types of mechanoreceptors from mice and tactile-specialist birds. This effect is observed at the level of mechanosensitive Piezo2 channels and can be replicated in heterologous systems using Piezo2 orthologs from different species. The cold sensitivity of Piezo2 is dependent on its blade domains, which render the channel resistant to cold-induced perturbations of the physical properties of the plasma membrane and give rise to a different mechanism of mechanical activation than that of Piezo1. Our data reveal that Piezo2 is an evolutionarily conserved mediator of thermal–tactile integration in cutaneous mechanoreceptors.

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Section: Discussionmentioning

confidence: 68%

Piezo2 integrates mechanical and thermal cues in vertebrate mechanoreceptors

Wang

Nikolaev

Gracheva

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…GABA A responses can be evoked both in the dorsal root as well as in the sciatic nerve, demonstrating the presence of these receptors on the central and peripheral axon (Bhisitkul et al, 1987). GABA A receptors located at central terminals of primary afferents in the spinal dorsal horn respond to GABA-release from spinal interneurons and induce presynaptic inhibition of synaptic inputs, which in most sensory systems is responsible for contrast enhancement and gain control (Zimmerman et al, 2019). Activation of these GABA A receptors by GABA released at axo-axonic synapses induces Cl − efflux that causes primary afferent depolarization.…”

Section: Ligand-gated Chloride Channelsmentioning

confidence: 99%

“…GABA A -mediated inhibition leads to tactile hypersensitivity and impaired texture discrimination (Zimmerman et al, 2019). The descending projections can set pain thresholds based on internal and emotional states, with acute stress and expected pain producing analgesia, while chronic stress and anxiety facilitate pain (Porreca et al, 2002;Basbaum et al, 2009;Jennings et al, 2014;Francois et al, 2017).…”

Section: Ligand-gated Chloride Channelsmentioning

confidence: 99%

Chloride – The Underrated Ion in Nociceptors

et al. 2020

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In contrast to pain processing neurons in the spinal cord, where the importance of chloride conductances is already well established, chloride homeostasis in primary afferent neurons has received less attention. Sensory neurons maintain high intracellular chloride concentrations through balanced activity of Na +-K +-2Cl − cotransporter 1 (NKCC1) and K +-Cl − cotransporter 2 (KCC2). Whereas in other cell types activation of chloride conductances causes hyperpolarization, activation of the same conductances in primary afferent neurons may lead to inhibitory or excitatory depolarization depending on the actual chloride reversal potential and the total amount of chloride efflux during channel or transporter activation. Dorsal root ganglion (DRG) neurons express a multitude of chloride channel types belonging to different channel families, such as ligand-gated, ionotropic γ-aminobutyric acid (GABA) or glycine receptors, Ca 2+-activated chloride channels of the anoctamin/TMEM16, bestrophin or tweetyhomolog family, CLC chloride channels and transporters, cystic fibrosis transmembrane conductance regulator (CFTR) as well as volume-regulated anion channels (VRACs). Specific chloride conductances are involved in signal transduction and amplification at the peripheral nerve terminal, contribute to excitability and action potential generation of sensory neurons, or crucially shape synaptic transmission in the spinal dorsal horn. In addition, chloride channels can be modified by a plethora of inflammatory mediators affecting them directly, via protein-protein interaction, or through signaling cascades. Since chloride channels as well as mediators that modulate chloride fluxes are regulated in pain disorders and contribute to nociceptor excitation and sensitization it is timely and important to emphasize their critical role in nociceptive primary afferents in this review.

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“…For example, GABA is synthesized in fibroblasts and likely liberated upon injuries causing skin disruption, and GABA A receptor-mediated nociceptor excitation is well accepted [ 83 , 84 ]. In addition, GABA A receptors, at presynaptic terminals in the superficial dorsal horn, can be targeted for presynaptic inhibition, which sets a brake to mechanical hypersensitivity [ 85 ]. However, whether GABA has excitatory or inhibitory effects largely depends on the actual concentration of intracellular chloride in these neurons (for review see [ 51 ]).…”

Section: Discussionmentioning

confidence: 99%

Selected Ionotropic Receptors and Voltage-Gated Ion Channels: More Functional Competence for Human Induced Pluripotent Stem Cell (iPSC)-Derived Nociceptors

et al. 2020

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Preclinical research using different rodent model systems has largely contributed to the scientific progress in the pain field, however, it suffers from interspecies differences, limited access to human models, and ethical concerns. Human induced pluripotent stem cells (iPSCs) offer major advantages over animal models, i.e., they retain the genome of the donor (patient), and thus allow donor-specific and cell-type specific research. Consequently, human iPSC-derived nociceptors (iDNs) offer intriguingly new possibilities for patient-specific, animal-free research. In the present study, we characterized iDNs based on the expression of well described nociceptive markers and ion channels, and we conducted a side-by-side comparison of iDNs with mouse sensory neurons. Specifically, immunofluorescence (IF) analyses with selected markers including early somatosensory transcription factors (BRN3A/ISL1/RUNX1), the low-affinity nerve growth factor receptor (p75), hyperpolarization-activated cyclic nucleotide-gated channels (HCN), as well as high voltage-gated calcium channels (VGCC) of the CaV2 type, calcium permeable TRPV1 channels, and ionotropic GABAA receptors, were used to address the characteristics of the iDN phenotype. We further combined IF analyses with microfluorimetric Ca2+ measurements to address the functionality of these ion channels in iDNs. Thus, we provide a detailed morphological and functional characterization of iDNs, thereby, underpinning their enormous potential as an animal-free alternative for human specific research in the pain field for unveiling pathophysiological mechanisms and for unbiased, disease-specific personalized drug development.

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Distinct Modes of Presynaptic Inhibition of Cutaneous Afferents and Their Functions in Behavior

Cited by 60 publications

References 61 publications

Piezo2 integrates mechanical and thermal cues in vertebrate mechanoreceptors

Piezo2 integrates mechanical and thermal cues in vertebrate mechanoreceptors

Chloride – The Underrated Ion in Nociceptors

Selected Ionotropic Receptors and Voltage-Gated Ion Channels: More Functional Competence for Human Induced Pluripotent Stem Cell (iPSC)-Derived Nociceptors

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