Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, IL, USA; Dept. of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, IL, USA; Dept. of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA; Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, USA; Institute of Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
Neurobiol Dis. 2024 Oct 1;200:106641. doi: 10.1016/j.nbd.2024.106641. Epub 2024 Aug 17.
STriatal-Enriched protein tyrosine Phosphatase (STEP) is a brain-specific tyrosine phosphatase that is associated with numerous neurological and neuropsychiatric disorders. STEP dephosphorylates and inactivates various kinases and phosphatases critical for neuronal function and health including Fyn, Pyk2, ERK1/2, p38, and PTPα. Importantly, STEP dephosphorylates NMDA and AMPA receptors, two major glutamate receptors that mediate fast excitatory synaptic transmission. This STEP-mediated dephosphorylation leads to their internalization and inhibits both Hebbian synaptic potentiation and homeostatic synaptic scaling. Hence, STEP has been widely accepted to weaken excitatory synaptic strength. However, emerging evidence implicates a novel role of STEP in neuronal hyperexcitability and seizure disorders. Genetic deletion and pharmacological blockade of STEP reduces seizure susceptibility in acute seizure mouse models and audiogenic seizures in a mouse model of Fragile X syndrome. Pharmacologic inhibition of STEP also decreases hippocampal activity and neuronal intrinsic excitability. Here, we will highlight the divergent roles of STEP in excitatory synaptic transmission and neuronal intrinsic excitability, present the potential underlying mechanisms, and discuss their impact on STEP-associated neurologic and neuropsychiatric disorders.
纹状体丰富的蛋白酪氨酸磷酸酶（STEP）是一种脑特异性的酪氨酸磷酸酶，与许多神经和神经精神疾病有关。STEP 去磷酸化并使包括 Fyn、Pyk2、ERK1/2、p38 和 PTPα 在内的多种对神经元功能和健康至关重要的激酶和磷酸酶失活。重要的是，STEP 去磷酸化 NMDA 和 AMPA 受体，这两种介导快速兴奋性突触传递的主要谷氨酸受体。这种 STEP 介导的去磷酸化导致它们内化，并抑制 Hebbian 突触增强和同型突触缩放。因此，STEP 已被广泛认为会削弱兴奋性突触强度。然而，新出现的证据表明 STEP 在神经元过度兴奋和癫痫障碍中具有新的作用。STEP 的基因缺失和药理学阻断可降低急性癫痫小鼠模型中的癫痫易感性和脆性 X 综合征小鼠模型中的听觉性癫痫发作。STEP 的药理学抑制也可降低海马体活动和神经元内在兴奋性。在这里，我们将重点介绍 STEP 在兴奋性突触传递和神经元内在兴奋性中的不同作用，介绍潜在的潜在机制，并讨论它们对与 STEP 相关的神经和神经精神疾病的影响。
