Administration of a novel high affinity PICK1 PDZ domain inhibitor attenuates cocaine seeking in rats

Turner, Cortney A.; Luca, Marta De; Wolfheimer, Jordan; Hernandez, Nicole S.; Madsen, Kenneth L.; Schmidt, Heath D.

doi:10.1016/j.neuropharm.2019.107901

Cited by 12 publications

(14 citation statements)

References 50 publications

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“…We did not find any effect of prefrontal PICK1 knockdown on sucrose or cocaine taking. This is consistent with previous work in our lab showing that prefrontal GRIP knockdown had no effect on fixed ratio measures of reward administration, 18 and with existing literature showing no effect of PICK1 inhibition on natural reinforcement 46,47 . Disruptions to glutamatergic signalling mechanisms have not been reported to affect sucrose seeking, 48,49 initial fixed ratio measures of self‐administration, 50,51 or extinction, 52 suggesting that glutamate is more important for cocaine seeking than sucrose or drug taking.…”

Section: Discussionsupporting

confidence: 91%

“…This is the first study to examine the possibility of sex differences in the role of PICK1. The results for males are consistent with past literature showing increased reinstatement after PICK1 antagonism, 46 elevated levels of GluA2‐lacking AMPARs after the removal of GluA2‐containing AMPARs, 12 and the importance of PFC to NAc glutamatergic transmission in addiction‐like behaviour 7,47,57 . Very little of this work has been replicated in females, and it is not known if females rely on the same molecular pathways for PICK1‐mediated plasticity as do males.…”

Section: Discussionsupporting

confidence: 89%

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Sex‐specific role for prefrontal cortical protein interacting with C kinase 1 in cue‐induced cocaine seeking

et al. 2021

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Disruption of prefrontal glutamate receptor interacting protein (GRIP), which anchors GluA2‐containing AMPA receptors (AMPARs) into the synaptic membrane, potentiates cue‐induced cocaine seeking in both males and females. Protein interacting with C kinase 1 (PICK1) plays an opposing role to that of GRIP, removing AMPARs from the synapse. Consistent with our hypothesis that disruption of PICK1 in the mPFC would lead to a decrease in addiction‐like behaviour, we found that conditional deletion of PICK1 in the mPFC attenuates cue‐induced cocaine seeking in male mice. However, prefrontal PICK1 deletion had the opposite effect in females, leading to an increase in cue‐induced reinstatement of cocaine seeking. We did not see any effects of PICK1 knockdown on sucrose taking or seeking, suggesting the sex‐specific effects do not generalise to natural reinforcers. These findings suggest the role of PICK1 in the prefrontal cortex of females may not be consistent with its accepted role in males. To determine whether these sex differences were influenced by gonadal hormones, we gonadectomised a cohort of males and found that removal of circulating androgens eliminated the effect of prefrontal PICK1 knockdown. As there was no effect of gonadectomy on its own on any of the behavioural measures collected, our results suggest that androgens may be involved in compensatory downstream effects of PICK1 knockdown. Taken together, these results highlight the need for consideration of sex as a biological variable when examining mechanisms underlying all behaviours, as convergent sex differences can reveal different mechanisms where behavioural sex differences do not exist.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 89%

Sex‐specific role for prefrontal cortical protein interacting with C kinase 1 in cue‐induced cocaine seeking

et al. 2021

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“…In analogy, PICK1 seems to serve a specific role in potentiating AMPAR function during acquisition and reacquisition of cocaine dependence (Bellone & Luscher, ; Famous et al , ; Schmidt et al , ; Jensen, ), suggesting that PICK1 is a promising target in addiction. Indeed, Tat‐P 4 ‐(C5) 2 strongly reduces cocaine reinstatement in a self‐administering paradigm (Turner et al , ). Moreover, PICK1 has been evoked as a putative target in ischemia (Dixon et al , ), Alzheimer's disease (Alfonso et al , ), and Parkinson's disease (He et al , ).…”

Section: Discussionmentioning

confidence: 99%

A high‐affinity, bivalent PDZ domain inhibitor complexes PICK 1 to alleviate neuropathic pain

et al. 2020

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Maladaptive plasticity involving increased expression of AMPAtype glutamate receptors is involved in several pathologies, including neuropathic pain, but direct inhibition of AMPARs is associated with side effects. As an alternative, we developed a cell-permeable, high-affinity (~2 nM) peptide inhibitor, Tat-P 4 -(C5) 2 , of the PDZ domain protein PICK1 to interfere with increased AMPAR expression. The affinity is obtained partly from the Tat peptide and partly from the bivalency of the PDZ motif, engaging PDZ domains from two separate PICK1 dimers to form a tetrameric complex. Bivalent Tat-P 4 -(C5) 2 disrupts PICK1 interaction with membrane proteins on supported cell membrane sheets and reduce the interaction of AMPARs with PICK1 and AMPA-receptor surface expression in vivo. Moreover, Tat-P 4 -(C5) 2 administration reduces spinal cord transmission and alleviates mechanical hyperalgesia in the spared nerve injury model of neuropathic pain. Taken together, our data reveal Tat-P 4 -(C5) 2 as a novel promising lead for neuropathic pain treatment and expand the therapeutic potential of bivalent inhibitors to non-tandem protein-protein interaction domains.

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“…30 Furthermore, Tat-P 4 -(C5) 2 demonstrates efficacy in reducing addiction-like behavior in mice. 75 Tat-P 4 -(C5) 2 interacts with the binding pocket of the PDZ domain as well as negatively charged residues on of β B- β C loop which introduces an additional layer of stabilization. Our structural analysis against PSD-95 PDZ highlights the unique structure of PICK1 PDZ at the β B- β C loop.…”

Section: Discussionmentioning

confidence: 99%

The electrostatic allostery could be the trigger for the changes in dynamics for the PDZ domain of PICK1

Stevens¹,

He²

2020

Preprint

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The PDZ domain is a highly abundant protein-protein interaction domain that exists in many signaling proteins, such as PICK1. Despite the highly conserved structure of the PDZ family, the PDZ family has an extremely low sequence identity, making each PDZ domain unique. PICK1 is the only protein in the human genome that is comprised of a PDZ domain and a BAR domain. PICK1 regulates surface membrane proteins and has been identified as an integral player in drug addiction. Like many PDZ-containing proteins, PICK1 is positively regulated by its PDZ domain and has thus drawn attention to be a potential drug target to curb the effects of substance abuse. The goal of this study is to use all-atom molecular dynamics simulations and the electrostatic analysis program, DelPhi, to better understand the unique interactions and dynamic changes in the PICK1 PDZ domain upon complex formation. Our results demonstrated that the PICK1 PDZ domain shares similar canonical PDZ-ligand hydrogen bonding networks and fluctuations of the carboxylate-binding loop to other PDZ domains. Furthermore, our results are unique to the PICK1 PDZ domain as we reveal that the binding of ligand opens up the binding pocket and, at the same time, reduces the fluctuations of both the central part of the binding pocket and the short loop region between the αA-helix and βC-strand. More importantly, the binding of ligand resulted in charge redistribution at the binding pocket region as well as the N- and C-termini of the PDZ domain that are not a part of the binding pocket. These results suggest that the electrostatic allostery resulted from ligand binding could be the key factor leading to the changes in dynamics which may be associated with the activation of PICK1. Based on these results, an effective drug to target PDZ domain must not only stably bind to the PICK1 PDZ domain but also prevent the electrostatic allostery of the PDZ domain.

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Administration of a novel high affinity PICK1 PDZ domain inhibitor attenuates cocaine seeking in rats

Cited by 12 publications

References 50 publications

Sex‐specific role for prefrontal cortical protein interacting with C kinase 1 in cue‐induced cocaine seeking

Sex‐specific role for prefrontal cortical protein interacting with C kinase 1 in cue‐induced cocaine seeking

A high‐affinity, bivalent PDZ domain inhibitor complexes PICK 1 to alleviate neuropathic pain

The electrostatic allostery could be the trigger for the changes in dynamics for the PDZ domain of PICK1

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