Biological complexity: protecting synapses (Introduction)

by David Turell , Friday, October 22, 2021, 15:03 (917 days ago) @ David Turell

Another chain of auto-reactions of controlling molecules:

https://www.science.org/doi/10.1126/scisignal.aaz4112

"Another G for GABAB receptor
Activation of GABABR, the G protein–coupled receptor for the inhibitory neurotransmitter GABA, is thought to be neuroprotective through exclusive engagement of Gi/o. However, Wang et al. found that GABABR also engaged G13 to differentially activate the MAPK pathway kinase JNK. In cultured cerebellar granule neurons, this G13-mediated pathway increased the abundance of the postsynaptic scaffolding protein PSD95 and enhanced neuronal survival under low-potassium conditions. The authors further uncovered biological synergy between the two G protein–mediated pathways, with different kinetics in agonist responses. The findings reveal how GABA can mediate neuroprotection through multiple synergistic pathways that depend on distinct G proteins."

"Abstract
G protein–coupled receptors (GPCRs) activate various mitogen-activated protein kinase (MAPK) pathways to regulate critical cell functions. β-Arrestins mediate this mechanism for most GPCRs but not the GABAB receptor (GABABR). When coupled to the G protein Gi/o, GABABR phosphorylates the kinases ERK1 and ERK2. Here, we uncovered a distinct β-arrestin–independent mechanism of MAPK pathway activation by GABABR. We found that GABABR also phosphorylated the kinase JNK downstream of activation of the small guanosine triphosphatases (GTPases) RhoA and Rac1 in primary mouse neurons. However, instead of Gi/o proteins, activation of this RhoA/Rac1-JNK pathway was mediated by G13. This pathway promoted the phosphorylation and accumulation of the postsynaptic scaffolding protein PSD95 and GABABR-mediated neuroprotection in granule neurons. In addition, this pathway synergized with a previously reported GABABR-mediated neuroprotection mediated by a Gi/o-dependent mechanism. GABABR agonists activated G13 with slower kinetics and lower potency than with which they activated Gi/o. Our findings reveal distinct, β-arrestin–independent, context-specific synergistic mechanisms of MAPK activation by G protein–mediated GPCR signaling." (my bold)

Comment: note the use of the word pathway in which one pathway controls or activates another. Pathways are a series of protein reactions working in steps from beginning to end of molecular reactions mediated by enzymes. A perfect example of reactions to present chemical conditions causing new steps. All automatically con trolled.