Dendritic spine dynamics--a key role for kalirin-7 - PubMed (original) (raw)

Review

Dendritic spine dynamics--a key role for kalirin-7

Peter Penzes et al. Trends Neurosci. 2008 Aug.

Abstract

Changes in the structure and function of dendritic spines contribute to numerous physiological processes such as synaptic transmission and plasticity, as well as behavior, including learning and memory. Moreover, altered dendritic spine morphogenesis and plasticity is an endophenotype of many neurodevelopmental and neuropsychiatric disorders. Hence, the molecular mechanisms that control spine plasticity and pathology have been under intense investigation over the past few years. A series of recent studies has improved our understanding of spine dynamics by establishing kalirin-7 as an important regulator of dendritic spine development as well as structural and functional plasticity, providing a model for the molecular control of structural plasticity and implicating kalirin-7 in synaptic pathology in several disorders including schizophrenia and Alzheimer's disease.

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Figures

Figure 1

Kalirin-7 is a postsynaptic regulator of spine morphogenesis. (a) Domain structure of kalirin-7; the Dbl-homology (DH) and pleckstrin homology (PH) domains provide the GEF activity; at its C terminus, kalirin-7 contains a unique 20 amino acid sequence ending in a PDZ domain-binding motif (STYV). The GEF domain activates Rac1, and controls spine remodeling by modulating actin cytoskeletal rearrangements. (b) In pyramidal neurons, kalirin-7 is targeted to dendritic spines. Images show GFP-filled neurons cotransfected with other constructs. (c) Kalirin-7 regulates dendritic spine morphogenesis and maintenance in pyramidal neurons: its overexpression promotes spine formation and enlargement; its RNAi-mediated knockdown causes spine shrinkage and loss.

Figure 2

Mechanisms of spine development, plasticity and stability: control by kalirin-7. (a) In young hippocampal pyramidal neurons, kalirin-7 controls rapid spiny synapse maturation induced by ephrinB/EphB trans-synaptic signaling. (b) In mature cortical pyramidal neurons, kalirin-7 mediates activity-dependent spine plasticity. (c) In cortical pyramidal neurons, kalirin-7 mediates coordination of synaptic adhesion with spine morphology downstream of N-cadherin.

Figure 3

Synaptic signaling networks: regulators and targets of kalirin-7. Signaling by NMDAR and G-protein-coupled receptors modulates kalirin-7 GEF activity (red). Interactions with EphB, Arf6 and PDZ domain-containing proteins control kalirin-7 localization. The major signaling output (black) of kalirin-7 is through Rac1 and PAK; however, it also interacts with and modulates other proteins, including iNOS and DISC1. Hence, kalirin-7 signaling controls multiple aspects of spine plasticity and might be involved in spine pathology associated with CNS disorders. Proteins in bold letters are discussed in the text.

Figure 4

Roles of kalirin-7 in postsynaptic signaling. (a) Signal amplification by kalirin-7: each kalirin-7 molecule activates several Rac1 molecules. (b) Signal channeling through spatial localization and proximity of the signaling proteins, facilitated by the direct interactions of the components. (c) Integration of multiple signaling inputs onto kalirin-7. (d) Coordinated regulation of spine structure and synaptic function. Each signaling aspect is shown individually.

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Dendritic spine dynamics--a key role for kalirin-7 - PubMed (original) (raw)