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PIEZO2 is a trimeric mechanically-gated ion channel expressed by most sensory neurons in the dorsal root ganglia. Mechanosensitive PIEZO2 channels are also genetically required for normal touch sensation in both mice and humans. We previously showed that PIEZO2 channels are also strongly modulated by membrane voltage. Specifically, it is only at very positive voltages that all channels are available for opening by mechanical force. Conversely, most PIEZO2 channels are blocked at normal negative resting membrane potentials. The physiological function of this unusual biophysical property of PIEZO2 channels, however, remained unknown. We characterized the biophysical properties of three PIEZO2 ion channel mutations at an evolutionarily conserved arginine (R2756). Using genome engineering in mice we generated Piezo2 R2756H/R2756H and Piezo2 R2756K/R2756K knock-in mice to characterize the physiological consequences of altering PIEZO2 voltage sensitivity in vivo. We measured endogenous mechanosensitive currents in sensory neurons isolated from the dorsal root ganglia and characterized mechanoreceptor and nociceptor function using electrophysiology. Mice were also assessed behaviourally and morphologically. Mutations at the conserved Arginine (R2756) dramatically changed the biophysical properties of the channel relieving voltage block and lowering mechanical thresholds for channel activation. Piezo2R2756H/R2756H and Piezo2R2756K/R2756K knock-in mice that were homozygous for gain-of-function mutations were viable and were tested for sensory changes. Surprisingly, mechanosensitive currents in nociceptors, neurons that detect noxious mechanical stimuli, were substantially sensitized in Piezo2 knock-in mice, but mechanosensitive currents in most mechanoreceptors that underlie touch sensation were only mildly affected by the same mutations. Single-unit electrophysiological recordings from sensory neurons innervating the glabrous skin revealed that rapidly-adapting mechanoreceptors that innervate Meissner's corpuscles exhibited slightly decreased mechanical thresholds in Piezo2 knock-in mice. Consistent with measurements of mechanically activated currents in isolated sensory neurons essentially all cutaneous nociceptors, both fast conducting Aδ-mechanonociceptors and unmyelinated C-fibre nociceptors were substantially more sensitive to mechanical stimuli and indeed acquired receptor properties similar to ultrasensitive touch receptors in Piezo2 knock-in mice. Mechanical stimuli also induced enhanced ongoing activity in cutaneous nociceptors in Piezo2 knock-in mice and hyper-sensitive PIEZO2 channels were sufficient alone to drive ongoing activity, even in isolated nociceptive neurons. Consistently, Piezo2 knock-in mice showed substantial behavioural hypersensitivity to noxious mechanical stimuli. Our data indicate that ongoing activity and sensitization of nociceptors, phenomena commonly found in human chronic pain syndromes, can be driven by relieving the voltage-block of PIEZO2 ion channels. Indeed, membrane depolarization caused by multiple noxious stimuli may sensitize nociceptors by relieving voltage-block of PIEZO2 channels. [ABSTRACT FROM AUTHOR]

Introduction: Introduction: CD36 is a membrane protein that functions as a lingual receptor for lipids. The soluble CD36 fraction (sCD36) may correlate oral fatty acid fat taste sensitivity to body mass index (BMI) and adiposity. Objectives: to determine if the oral fatty acid taste sensitivity in healthy young individuals of both sexes is related to serum sCD36 levels, adiposity and BMI. Methods: a cross-sectional study was conducted in 72 healthy young individuals (18-25 years). Serum sCD36 was quantified for all subjects. Oral fatty acid taste sensitivity was determined using an ascending series of the three-alternate forced choice methodology. Additionally, BMI was calculated using anthropometry, and adiposity was determined by bioelectric impedance analysis. Results: there was a positive correlation between BMI and the oral fatty acid taste sensitivity threshold (r = 0.277, p < 0.05) and a negative correlation between BMI and serum sCD36 levels (r = -0.035, p < 0.01). Adiposity negatively correlated with the sCD36 levels only in women (r = -0.359, p < 0.05). The threshold for oral sensitivity to fatty acids in overweight individuals was 1.0 (IQR 1.16) mM vs 0.2 (IQR 0.29) mM in healthy weight individuals (p < 0.05), while sCD36 levels were 26.1 pg/ml (IQR 32.9) and 77.97 pg/ml (IQR 560.66) in overweight and normal weight individuals, respectively (p < 0.05). Conclusions: BMI positively correlates with the oral sensitivity threshold of fatty acids and negatively correlates with serum sCD36 levels. The threshold of oral sensitivity to fatty acids was significantly higher in overweight subjects, while sCD36 levels were significantly higher in the group of normal weight individuals. [ABSTRACT FROM AUTHOR]

PIEZO2 is a trimeric mechanically-gated ion channel expressed by most sensory neurons in the dorsal root ganglia. Mechanosensitive PIEZO2 channels are also genetically required for normal touch sensation in both mice and humans. We previously showed that PIEZO2 channels are also strongly modulated by membrane voltage. Specifically, it is only at very positive voltages that all channels are available for opening by mechanical force. Conversely, most PIEZO2 channels are blocked at normal negative resting membrane potentials. The physiological function of this unusual biophysical property of PIEZO2 channels, however, remained unknown. We characterized the biophysical properties of three PIEZO2 ion channel mutations at an evolutionarily conserved arginine (R2756). Using genome engineering in mice we generated Piezo2R2756H/R2756H and Piezo2R2756K/R2756K knock-in mice to characterize the physiological consequences of altering PIEZO2 voltage sensitivity in vivo. We measured endogenous mechanosensitive currents in sensory neurons isolated from the dorsal root ganglia and characterized mechanoreceptor and nociceptor function using electrophysiology. Mice were also assessed behaviourally and morphologically. Mutations at the conserved Arginine (R2756) dramatically changed the biophysical properties of the channel relieving voltage block and lowering mechanical thresholds for channel activation. Piezo2R2756H/R2756H and Piezo2R2756K/R2756K knock-in mice that were homozygous for gain-of-function mutations were viable and were tested for sensory changes. Surprisingly, mechanosensitive currents in nociceptors, neurons that detect noxious mechanical stimuli, were substantially sensitized in Piezo2 knock-in mice, but mechanosensitive currents in most mechanoreceptors that underlie touch sensation were only mildly affected by the same mutations. Single-unit electrophysiological recordings from sensory neurons innervating the glabrous skin revealed that rapidly-adapting mechanoreceptors that innervate Meissner's corpuscles exhibited slightly decreased mechanical thresholds in Piezo2 knock-in mice. Consistent with measurements of mechanically activated currents in isolated sensory neurons essentially all cutaneous nociceptors, both fast conducting Aδ-mechanonociceptors and unmyelinated C-fibre nociceptors were substantially more sensitive to mechanical stimuli and indeed acquired receptor properties similar to ultrasensitive touch receptors in Piezo2 knock-in mice. Mechanical stimuli also induced enhanced ongoing activity in cutaneous nociceptors in Piezo2 knock-in mice and hyper-sensitive PIEZO2 channels were sufficient alone to drive ongoing activity, even in isolated nociceptive neurons. Consistently, Piezo2 knock-in mice showed substantial behavioural hypersensitivity to noxious mechanical stimuli. Our data indicate that ongoing activity and sensitization of nociceptors, phenomena commonly found in human chronic pain syndromes, can be driven by relieving the voltage-block of PIEZO2 ion channels. Indeed, membrane depolarization caused by multiple noxious stimuli may sensitize nociceptors by relieving voltage-block of PIEZO2 channels., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Introduction: Introduction: CD36 is a membrane protein that functions as a lingual receptor for lipids. The soluble CD36 fraction (sCD36) may correlate oral fatty acid fat taste sensitivity to body mass index (BMI) and adiposity. Objectives: to determine if the oral fatty acid taste sensitivity in healthy young individuals of both sexes is related to serum sCD36 levels, adiposity and BMI. Methods: a cross-sectional study was conducted in 72 healthy young individuals (18-25 years). Serum sCD36 was quantified for all subjects. Oral fatty acid taste sensitivity was determined using an ascending series of the three-alternate forced choice methodology. Additionally, BMI was calculated using anthropometry, and adiposity was determined by bioelectric impedance analysis. Results: there was a positive correlation between BMI and the oral fatty acid taste sensitivity threshold (r = 0.277, p < 0.05) and a negative correlation between BMI and serum sCD36 levels (r = -0.035, p < 0.01). Adiposity negatively correlated with the sCD36 levels only in women (r = -0.359, p < 0.05). The threshold for oral sensitivity to fatty acids in overweight individuals was 1.0 (IQR 1.16) mM vs 0.2 (IQR 0.29) mM in healthy weight individuals (p < 0.05), while sCD36 levels were 26.1 pg/ml (IQR 32.9) and 77.97 pg/ml (IQR 560.66) in overweight and normal weight individuals, respectively (p < 0.05). Conclusions: BMI positively correlates with the oral sensitivity threshold of fatty acids and negatively correlates with serum sCD36 levels. The threshold of oral sensitivity to fatty acids was significantly higher in overweight subjects, while sCD36 levels were significantly higher in the group of normal weight individuals.