PICK1: A differential regulator of glutamate receptor trafficking and AMPA receptor endocytosis

Work done in the lab of Dr. Samarjit Bhattacharyya at the Indian Institute of Science Education and Research Mohali.

About author

Dr. Namrata Ramsakha is originally from Orai (Uttar Pradesh). She holds two master’s degrees, one in Biotechnology from Jammu University and the other in Biomedical Sciences from ACBR (Delhi University). Driven by her passion for research, she pursued her doctoral studies in Cellular and Molecular Neuroscience at the Indian Institute of Science Education and Research Mohali under the guidance of Dr. Samarjit Bhattacharyya. Currently, she is a postdoctoral fellow in Dr. Ivo Spiegel’s lab at the Weizmann Institute of Science in Israel. Her research focuses on exploring experience-induced plasticity in the cortex. Outside of her scientific pursuits, Dr. Ramsakha finds joy in spending time with her adorable one-year-old daughter, Ineisha.

Interview

How would you explain your research outcomes to the non-scientific community?

Glutamate is an essential excitatory neurotransmitter that plays a crucial role in the developmental processes and experience-induced modifications in the brain. It acts via two types of receptors called ionotropic (iGlu) and metabotropic glutamate receptors (mGluRs). Within the mGluR family, group I mGluRs comprises mGluR1 and mGluR5. These receptors actively participate in diverse forms of experience–dependent synaptic plasticity, including learning and memory.

Dysregulation of group I mGluRs has been implicated in various neuropsychiatric disorders such as Fragile X syndrome and autism. Like many other G protein-coupled receptors (GPCRs), group I mGluRs also undergo desensitization and internalization following ligand exposure in the neuron. Proper trafficking of group I mGluRs is critical for their accurate spatiotemporal localization in the neuron as well as for the activity of these receptors. Improper trafficking can lead to abnormal signaling by these receptors, which might have severe pathological consequences. Despite this obvious significance, very little is known about the protein machineries that regulate the trafficking of these receptors, the regulatory mechanisms that control these protein machineries, and the physiological consequences of these regulatory mechanisms in the brain.

In this study, we have discovered a novel role of a protein called protein interacting with C kinase 1 (PICK1) in the internalization of mGluR1 and mGluR1-mediated AMPA receptor (AMPAR) endocytosis, which is believed to be the cellular mechanism underlying mGluR-dependent synaptic plasticity in hippocampal neurons. Hippocampus is an area in the brain that has been heavily implicated in the processing of some types of memory. We found that although PICK1 plays a vital role in stabilizing the surface expression of both mGluR1 and mGluR5, it is specifically involved in the internalization of mGluR1 and not in the internalization of mGluR5. Different regions of PICK1, including the N-terminal acidic motif, PDZ domain, and BAR domain, contribute to the agonist-induced internalization of mGluR1. Importantly, we demonstrate that PICK1-mediated internalization of mGluR1 is critical for the receptor’s resensitization, i.e., gaining back its activity after its desensitization. In the absence of PICK1, mGluR1 remained on the cell membrane as inactive receptors, unable to activate downstream signaling or induce AMPAR endocytosis.

Figure: Regulation of mGluR1 trafficking and mGluR1-dependent AMPAR endocytosis by post-synaptic scaffolding protein PICK1. Ligand-mediated activation of mGluR1 initiates G-protein-mediated signaling and results in the desensitization of the receptors. Subsequently, the desensitized receptors internalize and recycle back to the cell surface. PICK1 specifically regulates the surface expression as well as ligand-mediated endocytosis of mGluR1 and does not affect mGluR5 trafficking. In the absence of PICK1, mGluR1 remained on the cell membrane as inactive receptors, unable to activate MAP-kinase signaling or induce AMPAR endocytosis.

How do these findings contribute to your research area?

The intricate mechanisms responsible for regulating the internalization of group I mGluRs and mGluR-mediated AMPAR endocytosis, which is crucial for their proper functioning, are not fully understood. In our study, we aimed to shed light on this aspect by investigating the functional role of PICK1 in the trafficking of group I mGluRs and its physiological significance in the central nervous system. Importantly, our findings provide novel insights, as we are the first to demonstrate the distinct role of PICK1 in the internalization of mGluR1 and mGluR1-mediated AMPAR endocytosis, which might contribute to the function of mGluR1 in neuropsychiatric disorders.

“Our findings provide novel insights, as we are the first to demonstrate the distinct role of PICK1 in the internalization of mGluR1.”

What was the exciting moment during your research?

There were several exciting moments during my research. The most exciting one is when we found the specific regulatory role of PICK1 in the agonist-induced endocytosis of mGluR1 while there was no impact on the internalization of mGluR5. Afterwards, we were excited to observe that in the absence of PICK1 mGluR1-mediated AMPAR endocytosis was inhibited, but mGluR5-mediated AMPAR endocytosis was unaffected. This was the first protein present in the post-synaptic density region that showed differential regulation of mGluR1 and mGluR5 trafficking. These results demonstrate that PICK1 exerts distinct effects on the trafficking of mGluR1 and mGluR5, despite their classification within the same group.

What do you hope to do next?

Group I mGluRs are localized at the perisynaptic region of the post-synaptic membrane, where they interact with a variety of post-synaptic density (PSD) proteins. The PSD is a densely packed structure located beneath the post-synaptic membrane of excitatory synapses. In our previous work, we identified the involvement of specific PSD proteins such as Tamalin, Norbin, and sorting nexin 1 (SNX1) in the agonist-induced endocytosis and recycling of group I mGluRs. Moving forward, we are intrigued by understanding the interplay between these post-synaptic proteins, exploring how they communicate with each other to finely regulate the trafficking of group I mGluRs and the subsequent group I mGluR-mediated synaptic plasticity.

Where do you seek scientific inspiration from?

Throughout my scientific journey, I have been fortunate to encounter inspiring individuals who have influenced me greatly at different stages. One such person is Prof. Vani Brahmachari, my master’s teacher, whose guidance and teaching have left a lasting impact on me. Additionally, I owe a tremendous debt of gratitude to my Ph.D. supervisor, Dr. Samarjit Bhattacharyya who has not only nurtured my personal and professional growth but also taught me how to think critically and how to develop the skills necessary to tackle scientific inquiries with precision and thoroughness. Their mentorships have played a significant role in shaping me into an independent researcher.

How do you intend to help Indian science improve?

In my opinion, India has immense potential in producing outstanding scientists. However, we must allocate increased funding toward both fundamental and applied research domains. This objective can be achieved through enhanced collaboration between educational institutes and industries. I believe that organizing more and more scientific outreach programs and demonstrations would play a pivotal role in attracting students and nurturing their interest in science. I wish to continue my career in academia and research and encourage students to pursue scientific endeavors.

Reference

Ramsakha, Namrata, et al. “A vital role for PICK1 in the differential regulation of metabotropic glutamate receptor internalization and synaptic AMPA receptor endocytosis.” Journal of Biological Chemistry (2023): 104837.

https://www.sciencedirect.com/science/article/pii/S0021925823018653?via%3Dihub

Copy Editor

Ritvi Shah

Postgraduate at Vikram Sarabhai Institute

Postgraduate at Vikram Sarabhai Institute of Cell and Molecular Biology, Gujarat. She is a neuroscience enthusiast. Apart from that, she enjoys reading and trying her hand at sciart.

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