Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458.
Truhlsen Eye Institute, Durham Research Center I, University of Nebraska Medical Center, Omaha, NE 68198-5840.
Proc Natl Acad Sci U S A. 2021 Nov 9;118(45). doi: 10.1073/pnas.2106694118.
Cone photoreceptors mediate daylight vision in vertebrates. Changes in neurotransmitter release at cone synapses encode visual information and is subject to precise control by negative feedback from enigmatic horizontal cells. However, the mechanisms that orchestrate this modulation are poorly understood due to a virtually unknown landscape of molecular players. Here, we report a molecular player operating selectively at cone synapses that modulates effects of horizontal cells on synaptic release. Using an unbiased proteomic screen, we identified an adhesion GPCR Latrophilin3 (LPHN3) in horizontal cell dendrites that engages in transsynaptic control of cones. We detected and characterized a prominent splice isoform of LPHN3 that excludes a element with inhibitory influence on transsynaptic interactions. A gain-of-function mouse model specifically routing LPHN3 splicing to this isoform but not knockout of LPHN3 diminished Ca1.4 calcium channel activity profoundly disrupted synaptic release by cones and resulted in synaptic transmission deficits. These findings offer molecular insight into horizontal cell modulation on cone synaptic function and more broadly demonstrate the importance of alternative splicing in adhesion GPCRs for their physiological function.
视锥细胞在脊椎动物中介导日光视觉。神经递质在视锥突触中的释放变化编码视觉信息，并受到神秘水平细胞的负反馈的精确控制。然而，由于分子参与者的实际未知景观，协调这种调节的机制还知之甚少。在这里，我们报告了一种在视锥突触选择性作用的分子参与者，该参与者调节水平细胞对突触释放的影响。使用无偏的蛋白质组学筛选，我们在水平细胞树突中鉴定出一种粘附 GPCR Latrophilin3（LPHN3），它参与视锥细胞的突触间控制。我们检测并表征了 LPHN3 的一个突出剪接异构体，该异构体排除了对突触间相互作用具有抑制影响的元件。一种特异性将 LPHN3 剪接到该异构体的功能获得型小鼠模型，但不是敲除 LPHN3，极大地破坏了 Ca1.4 钙通道活性，严重破坏了视锥细胞的突触释放，并导致突触传递缺陷。这些发现为水平细胞对视锥突触功能的调节提供了分子见解，并更广泛地证明了在粘附 GPCR 中，选择性剪接对于其生理功能的重要性。
