Protease‐activated receptor‐1 modulates hippocampal memory formation and synaptic plasticity

Abstract

Protease-activated receptor-1 (PAR1) is an unusual G-protein coupled receptor (GPCR) that is activated through proteolytic cleavage by extracellular serine proteases. While previous work has shown that inhibiting PAR1 activation is neuroprotective in models of ischemia, traumatic injury, and neurotoxicity, surprisingly little is known about PAR1’s contribution to normal brain function. Here we used PAR1 −/− mice to investigate the contribution of PAR1 function to memory formation and synaptic function. We demonstrate that PAR1 −/− mice have deficits in hippocampus-dependent memory. We also show that while PAR1 −/− mice have normal baseline synaptic transmission at Schaffer collateral-CA1 synapses, they exhibit severe deficits in N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP). Mounting evidence indicates that activation of PAR1 leads to potentiation of NMDAR-mediated responses in CA1 pyramidal cells. Taken together, this evidence and our data suggest an important role for PAR1 function in NMDAR-dependent processes subserving memory formation and synaptic plasticity.

Proteinase-activated receptor 2 is involved in the behavioural changes associated with sickness behaviour

“…In addition, a recent study has revealed that a shift in G-protein signalling is a novel mechanism by which PAR1 modulates emotionally motivated behavioural learning in the amygdala (Bourgognon et al, 2013). The role of PAR1 has been further implicated in learning and memory with recent studies highlighting deficits in hippocampal-dependent learning and synaptic plasticity in PAR1 -/-mice compared to their littermate controls (Almonte et al, 2013). These findings indicate that PAR1 and PAR2 are not involved in locomotor activity and anxiety-like behaviour but implicate PAR1 in learning and memory.…”

Highly functionalized 2-oxopiperazine-based peptidomimetics: An approach to PAR1 antagonists

“…Found: C,67.51;H,7.65; N, 9.63. (2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl) 9,117.4,125.3 [3C (Pbf)], 126. 8, 128.2, 128.7, 128.9, 129.2, 129.5, 130.0, 130.4 [15CH (Ar) -3-(3-(3-benzyl-2-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl) ,7.28;N,8.93.…”

“…4.6.16. (5S,2,4,6, 9,117.5,125.3 [3C (Pbf)], 126. 8,128.1,128.7,129.0,129.4,129.9 [15CH (Ar) 7.52;N,8.71.…”

“…-indol-3-yl)ethyl-3-(3-(2-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl) 12.02. -3-(3-(2-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl) 9,117.5,125.3 [3C (Pbf)], 126. 8,127.3,128.1,128.7,128.9,129.0,129.3,129.4,129.9,130.3 [20CH (Ar) ,6.95;N,11.09.…”

“…Thrombin induces multiple effects on a variety of cells, such as: platelets [1][2][3][4], endothelial and smooth muscle cells [1,4,5], neurons and astrocytes in the nervous system [1,[4][5][6][7][8][9][10], immune and inflammatory cells [4,11,12], and tumor cells [13][14][15][16][17][18]. These effects are mediated by the activation of the protease-activated receptor 1 (PAR1) [19].…”