The Nobel Prize in Physiology or Medicine 2021 was awarded jointly to David Julius and Ardem Patapoutian for their discoveries of receptors for temperature and touch.

David Julius, Professor of Physiology at UCSF, studied mechanisms by which we sense heat, cold, and chemical irritants. Julius and colleagues developed a novel genome-wide screen for elevations in intracellular [Ca²⁺] in response to chemicals we perceive as “hot.” As reported in 1997, the screen identified cDNAs encoding TRPV1, a heat sensor acting as receptor for vanilloid compounds such as capsaicin.¹ This discovery was accompanied by the realization that TRPV1 is part of a large TRP gene superfamily related to the Transient Receptor Potential (trp) gene of the Drosophila visual transduction pathway. The discovery of TRPV1 was crucial to understanding how temperature variation induces electrical signals in the peripheral nervous system and helps process those signals centrally.

David Julius shared the Nobel award with Ardem Patapoutian, Professor of Neuroscience at Scripps Research Institute, La Jolla, California, USA, whose research efforts focused on cellular sensors that detect mechanical stimuli and transduce them as intracellular and juxtacrine chemical signals. In 2010, Patapoutian and colleagues reported their discovery of the ion channels PIEZO1 and PIEZO2 (after píesi, Greek for “pressure”), using a novel cellular screen for mechanosensitive elevations in intracellular [Ca²⁺].² PIEZO1 and PIEZO2 are plasma membrane ion channels susceptible to activation by lateral stretch of the lipid bilayer membrane. This lateral stretch may arise from cell poking or indentation, cell matrix stretching, hydrostatic pressure change, osmotic pressure change (manifest as cell volume change), and also isovolumic cell shape change.² Additional perturbations that activate PIEZO channels include those involved in our tactile sensation of light touch, pressure, and pain, as well as cellular responses to fluid flow and to (ultra)sound. Further studies have demonstrated that PIEZO1 and PIEZO2 regulate other crucial physiological processes including blood pressure, respiration, and urinary bladder control. Endogenous and exogenous chemical ligands can directly activate PIEZO channels or modulate their sensitivity to mechanical stimuli.

The 2021 Nobel Prize in Physiology or Medicine is relevant to hematology in several ways. The first connection is between TRPV1 and sickle cell disease (SCD). Pain is the principal cause of emergency department visits, hospitalizations, and everyday suffering in SCD. Both patients and transgenic mice with SCD display chronic mechanical, thermal, and chemical hypersensitivity, which may be mediated by TRPV1 channel signaling.^{3, 4} Indeed, the selective TRPV1 antagonist, A-425619, has been reported to reverse mechanical sensitization and to attenuate mechanical behavioral hypersensitivity in SCD mice.⁴ Oral administration to SCD mice of the TRPV1 agonist, capsaicin, which activates somatosensory nerves through TRPV1 binding, was shown to dramatically alleviate acute vaso-occlusive events and to significantly reduce ensuing chronic liver and kidney damage.⁴ Thus, pharmacological manipulation of TRPV1 activity may provide a promising approach to treat both the pain symptoms and the ischemic damage of SCD.

The connections between the mechanoreceptor PIEZO1 and hemolytic anemias are multiple. In 2012–2013, PIEZO1 was identified by exome sequencing as a causative gene of both isolated and syndromic forms of dehydrated hereditary stomatocytosis (DHS, also known as hereditary xerocytosis).^{5, 6} DHS is an autosomal dominant hemolytic anemia characterized by high reticulocyte count, tendency to macrocytosis, and mild jaundice. It is characterized by many other variably penetrant clinical features, including perinatal edema, severe thromboembolic complications after splenectomy, and hepatic iron overload (Figure 1). The phenotype of DHS patients ranges from asymptomatic to mild anemia.⁷ The main characteristic of the erythrocyte is cell dehydration caused by the loss of cellular K, which can be assessed by atomic absorption spectroscopy, osmotic fragility, or ektacytometry. PIEZO1 mutations in DHS lead to a gain-of-function (GoF) phenotype, either by slowing inactivation kinetics of the ion channel and/or by facilitating channel opening in response to physiological stimuli (Figure 1).^{7, 8} PIEZO1 is believed to be the key sensor of red cell membrane curvature, signaling modulation of intracellular ion content, and cell volume as a function of mechanical forces and constraints in capillaries and venules.

Red cell dehydration is an important factor in SCD pathophysiology. Three major ion transport pathways are involved in sickle cell dehydration: the K-Cl cotransporters (KCCs), the Gardos channel (KCNN4), and Psickle, the deoxyhemoglobin S polymerization-induced cation permeability found only in red cells of SCD patients, and most likely mediated by PIEZO1.⁹ Additionally, PIEZO1 may mediate a major fraction of the increased cation permeability of hereditary spherocytosis RBCs.¹⁰

The PIEZO1 E756del variant, present in up to 30% of individuals of African ancestry, was first characterized by delayed PIEZO1 ion channel inactivation and by very mild dehydration of RBC,¹¹ and was associated with RBC dehydration in patients with SCD.¹² However, subsequent studies have failed to document increased red cell dehydration^{13, 14} or increased Psickle activity¹⁴ in SCD red cells heterozygous or homozygous for PIEZO1 E756del.

The PIEZO1 E756del variant was also associated with resistance to erythroid invasion by malarial parasites in vitro and in mice,¹¹ a finding subsequently confirmed by the association between the PIEZO1 E756del and decreased severity of Plasmodium falciparum malaria in human patients, possibly reflecting decreased red cell surface expression of the plasmodial virulence factor, PfEMP.¹³ The protection against severe malaria afforded by the PIEZO1 variant was not additive to that afforded by sickle trait.

PIEZO1 also influences erythropoiesis: PIEZO1 activation during erythroid differentiation slowed differentiation and reticulocyte maturation.¹⁵

Recent evidence highlights a role for PIEZO1 in regulation of iron metabolism. DHS patients can exhibit hyperferritinemia (and even hemosiderosis) accompanied by very low values of plasma hepcidin. Overexpression and chemical activation in hepatoma cell lines of the R2456H and R2488Q PIEZO1 GoF mutants induced stronger Ca²⁺ influx than in cells expressing WT PIEZO1. The increased Ca²⁺ signal was associated with ERK phosphorylation, inhibition of the BMP/SMADs pathway, and in decreased expression of HAMP, encoding hepcidin.¹⁶ PIEZO1 involvement in iron metabolism was further confirmed in constitutive and in macrophage-specific transgenic PIEZO1 GoF mice. By 1 year of age, these mice develop severe hepatic hemosiderosis with elevated serum ferritin and transferrin saturation, accompanied by increased erythrophagocytosis, erythropoiesis, and erythroferrone.¹⁷ Increased serum ferritin and transferrin saturation were also observed in the over-40 age subgroup of African Americans carrying the E756del variant in PIEZO1.

The discovery of PIEZO1 as the major cause of DHS has increased our knowledge of PIEZO1 functions in the erythroid system and in systemic iron metabolism. The links between red cell physiology, iron metabolism, and the sense of touch embodied by PIEZO1 were previously unforeseen. The link between TRPV1-mediated nociception and pain in SCD, though itself not surprising, revealed a relationship quite distinct from that initially hypothesized. These findings illustrate the close, mutual dependence of basic and translational research in our ongoing investigation of the pathobiology and treatment of human disease. Indeed, continued study of temperature receptors and mechanoreceptors may soon identify new druggable targets for the still challenging treatment of anemia and chronic iron overload.

2021 年诺贝尔生理学或医学奖联合授予 David Julius 和 Ardem Patapoutian，以表彰他们发现了温度和触觉感受器。

加州大学旧金山分校生理学教授 David Julius 研究了我们感知热、冷和化学刺激物的机制。Julius 及其同事开发了一种新的全基因组筛选，用于响应我们认为“热”的化学物质的细胞内 [Ca ²⁺ ]升高。正如 1997 年报道的那样，该筛选鉴定了编码 TRPV1 的 cDNA，TRPV1 是一种热传感器，可作为辣椒素等类香草化合物的受体。¹这一发现伴随着认识到 TRPV1 是与果蝇瞬时受体电位 ( trp ) 基因相关的大 TRP 基因超家族的一部分视觉转导通路。TRPV1 的发现对于了解温度变化如何在周围神经系统中诱导电信号并帮助集中处理这些信号至关重要。

大卫朱利叶斯与美国加利福尼亚州拉霍亚斯克里普斯研究所神经科学教授 Ardem Patapoutian 分享了诺贝尔奖，他的研究工作专注于检测机械刺激并将其转换为细胞内和并列化学信号的细胞传感器。2010 年，Patapoutian 及其同事报告了他们发现离子通道 PIEZO1 和 PIEZO2（在píesi之后，希腊语中的“压力”），使用一种新的细胞筛选来检测细胞内 [Ca ²⁺ ] 的机械敏感性升高。²PIEZO1 和 PIEZO2 是质膜离子通道，容易被脂质双层膜的横向拉伸激活。这种横向拉伸可能来自细胞戳或压痕、细胞基质拉伸、静水压力变化、渗透压变化（表现为细胞体积变化）以及等容细胞形状变化。²激活 PIEZO 通道的其他扰动包括与我们对轻触、压力和疼痛的触觉感觉有关的扰动，以及细胞对流体流动和（超）声音的反应。进一步的研究表明，PIEZO1 和 PIEZO2 调节其他重要的生理过程，包括血压、呼吸和膀胱控制。内源性和外源性化学配体可以直接激活 PIEZO 通道或调节它们对机械刺激的敏感性。

2021 年诺贝尔生理学或医学奖在多个方面与血液学相关。第一个联系是 TRPV1 和镰状细胞病 (SCD) 之间的联系。疼痛是 SCD 急诊就诊、住院和日常痛苦的主要原因。患有 SCD 的患者和转基因小鼠都表现出慢性机械、热和化学超敏反应，这可能是由 TRPV1 通道信号传导介导的。^{3, 4}事实上，据报道，选择性 TRPV1 拮抗剂 A-425619 可逆转 SCD 小鼠的机械致敏和减轻机械行为超敏反应。⁴向 SCD 小鼠口服 TRPV1 激动剂辣椒素，通过 TRPV1 结合激活体感神经，可显着减轻急性血管闭塞事件并显着减少随后的慢性肝和肾损伤。⁴因此，TRPV1 活性的药理学操作可能为治疗 SCD 的疼痛症状和缺血性损伤提供一种有前景的方法。

机械感受器 PIEZO1 与溶血性贫血之间的联系是多方面的。在 2012-2013 年，PIEZO1 通过外显子组测序被鉴定为脱水遗传性口细胞增多症（DHS，也称为遗传性干细胞增多症）的孤立和综合征形式的致病基因。^{5, 6} DHS 是一种常染色体显性溶血性贫血，其特征是网织红细胞计数高、有大红细胞症倾向和轻度黄疸。它的特点是许多其他不同的外显性临床特征，包括围产期水肿、脾切除术后严重的血栓栓塞并发症和肝铁超负荷（图 1）。DHS 患者的表型范围从无症状到轻度贫血。⁷红细胞的主要特征是由细胞 K 损失引起的细胞脱水，这可以通过原子吸收光谱、渗透脆性或细胞计数法来评估。DHS 中的 PIEZO1 突变导致功能增益 (GoF) 表型，通过减缓离子通道的失活动力学和/或通过促进通道开放以响应生理刺激（图 1）。^{7, 8} PIEZO1 被认为是红细胞膜曲率的关键传感器，是细胞内离子含量的信号调节以及细胞体积随毛细血管和小静脉中机械力和约束的函数。

红细胞脱水是SCD病理生理学中的一个重要因素。镰状细胞脱水涉及三种主要的离子转运途径：K-Cl 协同转运蛋白 (KCC)、Gardos 通道 (KCNN4) 和 Psickle，脱氧血红蛋白 S 聚合诱导的阳离子渗透性仅在 SCD 患者的红细胞中发现，大多数可能由 PIEZO1 介导。⁹此外，PIEZO1 可能介导遗传性球形红细胞增多症红细胞阳离子渗透性增加的主要部分。¹⁰

PIEZO1 E756del 变体存在于多达 30% 的非洲血统个体中，其最初的特征是 PIEZO1 离子通道失活延迟和红细胞非常轻度脱水，¹¹并且与 SCD 患者的红细胞脱水有关。¹²然而，随后的研究未能证明 PIEZO1 E756del 杂合或纯合的 SCD 红细胞中红细胞脱水增加^13、14或 Psickle 活性增加¹⁴。

PIEZO1 E756del 变体还与体外和小鼠体内对疟原虫对红细胞侵袭的抵抗力有关，¹¹这一发现随后被 PIEZO1 E756del 与人类患者恶性疟原虫疟疾严重程度降低之间的关联所证实，这可能反映了红细胞表面减少疟原虫毒力因子 PfEMP 的表达。¹³ PIEZO1 变体提供的针对严重疟疾的保护与镰状特性提供的保护没有叠加。

PIEZO1 也影响红细胞生成：红细胞分化过程中 PIEZO1 的激活减缓了分化和网织红细胞的成熟。¹⁵

最近的证据强调了 PIEZO1 在调节铁代谢中的作用。DHS 患者可表现出高铁蛋白血症（甚至含铁血黄素沉着症），同时血浆铁调素含量极低。与表达 WT PIEZO1 的细胞相比，R2456H 和 R2488Q PIEZO1 GoF 突变体在肝癌细胞系中的过表达和化学活化诱导更强的 Ca ^2+流入。增加的 Ca ²⁺信号与 ERK 磷酸化、BMP/SMADs 通路的抑制以及编码铁调素的HAMP表达降低有关。¹⁶在组成型和巨噬细胞特异性转基因 PIEZO1 GoF 小鼠中进一步证实了 PIEZO1 参与铁代谢。到 1 岁时，这些小鼠会出现严重的肝脏含铁血黄素沉着症，血清铁蛋白和转铁蛋白饱和度升高，同时伴有吞噬红细胞增多、红细胞生成和红细胞生成素增加。¹⁷在 PIEZO1 中携带 E756del 变体的 40 岁以上非洲裔美国人亚组中也观察到血清铁蛋白和转铁蛋白饱和度增加。

PIEZO1作为 DHS 的主要原因的发现增加了我们对 PIEZO1 在红系系统和全身铁代谢中的功能的了解。PIEZO1 所体现的红细胞生理学、铁代谢和触觉之间的联系是以前无法预料的。TRPV1 介导的伤害感受和 SCD 中的疼痛之间的联系虽然本身并不令人惊讶，但揭示了一种与最初假设的完全不同的关系。这些发现表明，在我们正在进行的人类疾病病理学和治疗研究中，基础研究和转化研究之间存在密切的相互依赖关系。事实上，对温度感受器和机械感受器的持续研究可能很快就会为仍然具有挑战性的贫血和慢性铁超负荷治疗确定新的药物靶点。