Developmental Changes in Calmodulin‐Kinase II Activity at Brain Synaptic Junctions: Alterations in Holoenzyme Composition

Abstract

Synaptic junctions (SJs) from rat forebrain were isolated at increasing postnatal ages and examined for endogenous protein kinase activities. Our studies focused on the postnatal maturation of the multifunctional protein kinase designated Ca2+/calmodulin-dependent protein kinase II (CaM-kinase II). This kinase is comprised of a major 50-kilodalton (kDa) and a minor 60-kDa subunit. Experiments examined the developmental properties of CaM-kinase II associated with synaptic plasma membranes (SPMs) and synaptic junctions (SJs), as well as the holoenzyme purified from cytosolic extracts. Large developmental increases in CaM-kinase II activity of SJ fractions were observed between postnatal days 6 and 20; developmental changes were examined for a number of properties including (a) autophosphorylation, (b) endogenous substrate phosphorylation, (c) exogenous substrate phosphorylation, and (d) immunoreactivity. Results demonstrated that forebrain CaM-kinase II undergoes a striking age-dependent change in subunit composition. In early postnatal forebrain the 60-kDa subunit constitutes the major catalytic and immunoreactive subunit of the holoenzyme. The major peak of CaM-kinase II activity in SJ fractions occurred at approximately postnatal day 20, a time near the end of the most active period of in vivo synapse formation. Following this developmental age, CaM-kinase II continued to accumulate at SJs; however, its activity was not as highly activated by Ca2+ plus calmodulin.

Postsynaptic Calcineurin Activity Downregulates Synaptic Transmission by Weakening Intracellular Ca2+Signaling Mechanisms in Hippocampal CA1 Neurons

“…Why does inhibiting CaN activity in young animals produce multiple results, i.e., prevent induction of LTD, LTP, and synaptic disinhibition (LTD of inhibitory synapses by tetanus)? We propose that although the developing pattern of Ca 2ϩ -dependent protein kinases in brain is similar to that for CaN, their expression is not synchronous (Turner et al, 1984;Kelly and Vernon, 1985;Kelly et al, 1987;Hashimoto, 1988;Yoshida et al, 1988;Hirata et al, 1991) such that shifting the equilibrium between kinases and CaN in postnatal versus adult brain produces different effects on synaptic plasticity. CaN activity may play a dual role in synaptic plasticity during postnatal development and is required for LTD and LTP.…”

Amphetamine sensitization elevates CaMKIIß mRNA

“…The a:b ratio changes throughout development. In the forebrain of a 10-day old rat, the ratio between a and b is 1:1, compared with an adult, where the ratio is 2.3:1 (Kelly et al, 1987;McGuinness et al, 1985;Miller and Kennedy, 1985). Increased CaMKII levels, especially of CaMKIIb, which are observed in schizophrenia patients and in amphetamine sensitized rats, may play a role in abnormal neurodevelopment and subsequent predisposition to schizophrenia (Novak et al, 2006).…”

Calcium/Calmodulin-Dependent Protein Kinase II

“…The forebrain of 5-day postnatal rats contains approx. 800% cytoplasmic CaM-kinase II, with ax (50 kDa) and /3(60 kDa) subunits in a molar ratio of about 1:4 [37]. Between days 5 and 20 there is a 10-fold increase in CaM-kinase II, with 80 % of the kinase now being particulate, and a 7: 1 ratio of a and , subunits [37].…”