Hippocampal Gαq/₁₁ but not Gαo-coupled receptors are altered in aging.
Normal aging may limit the signaling efficacy of certain GPCRs by disturbing the function of specific Gα-subunits and leading to deficient modulation of intracellular functions that subserve synaptic plasticity, learning and memory. Evidence suggests that Gαq/₁₁ is more sensitive to the effects of aging relative to other Gα-subunits, including Gαo. To test this hypothesis, the functionality of Gαq/₁₁ and Gαo were compared in the hippocampus of young (6 months) and aged (24 months) F344 × BNF₁ hybrid rats assessed for spatial learning ability. Basal GTPγS-binding to Gαq/₁₁ was significantly elevated in aged rats relative to young and but not reliably associated with spatial learning. mAChR stimulation of Gαq/₁₁ with oxotremorine-M produced equivocal GTPγS-binding between age groups although values tended to be lower in the aged hippocampus and were inversely related to basal activity. Downstream Gαq/₁₁ function was measured in hippocampal subregion CA₁ by determining changes in [Ca(2+)]i after mAChR and mGluR (DHPG) stimulation. mAChR-stimulated peak change in [Ca(2+)]i was lower in aged CA₁ relative to young while mGluR-mediated integrated [Ca(2+)]i responses tended to be larger in aged. GPCR modulation of [Ca(2+)]i was observed to depend on intracellular stores to a greater degree in aged than young. In contrast, measures of Gαo-mediated GTPγS-binding were stable across age, including basal, mAChR-, GABABR (baclofen)-stimulated levels. Overall, the data indicate that aging selectively modulates the activity of Gαq/₁₁ within the hippocampus leading to deficient modulation of [Ca(2+)]i following stimulation of mAChRs but these changes are not related to spatial learning.
Neuroscience Program, Wake Forest University Graduate School of Arts & Sciences, Medical Center Boulevard, Winston-Salem, NC 27157, USA. jmcquail@wakehealth.edu
Joseph A
JA
McQuail
Kathleen N
KN
Davis
Frances
F
Miller
Robert E
RE
Hampson
Samuel A
SA
Deadwyler
Allyn C
AC
Howlett
Michelle M
MM
Nicolle
D000375:Aging / Q000378:metabolism* / Q000523:psychology*; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D056547:CA1 Region, Hippocampal / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D058786:GABA-B Receptor Agonists / Q000494:pharmacology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D007858:Learning; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology; D010095:Oxotremorine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D012118:Resorcinols / Q000494:pharmacology; D013037:Spatial Behavior
D018690:Excitatory Amino Acid Agonists; D058786:GABA-B Receptor Agonists; D018721:Muscarinic Agonists; D012118:Resorcinols; D010095:Oxotremorine; C079215:3,5-dihydroxyphenylglycine; C042743:oxotremorine M; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D001418:Baclofen; D002118:Calcium; D005998:Glycine