Adam Smith’s Green Thumb and Malthus’ Three Horsemen: Cautionary tales from classical political economy

This essay identifies a contradiction between the flourishing interest in the environmental economics of the classical period and a lack of critical parsing of the works of its leading representatives. Its focus is the work of Adam Smith and Thomas Malthus. It offers a critical analysis of their contribution to environmental thought and surveys the work of their contemporary devotees. It scrutinizes Smith's contribution to what Karl Polanyi termed the "economistic fallacy," as well as his defenses of class hierarchy, the "growth imperative" and consumerism. It subjects to critical appraisal Malthus's enthusiasm for private property and the market system, and his opposition to market regulation. While Malthus's principal attraction to ecological economists lies in his having allegedly broadened the scope of economics, and in his narrative of scarcity, this article shows that he, in fact, narrowed the scope of the discipline and conceptualized scarcity in a reified and pseudo-scientific way

ERK1/2-Dependent Phosphorylation of GABA<inf>B1</inf>(S867/T872), Controlled by CaMKIIβ, Is Required for GABA<inf>B</inf> Receptor Degradation under Physiological and Pathological Conditions

GABAB receptor-mediated inhibition is indispensable for maintaining a healthy neuronal excitation/inhibition balance. Many neurological diseases are associated with a disturbed excitation/inhibition balance and downregulation of GABAB receptors due to enhanced sorting of the receptors to lysosomal degradation. A key event triggering the downregulation of the receptors is the phosphorylation of S867 in the GABAB1 subunit mediated by CaMKIIβ. Interestingly, close to S867 in GABAB1 exists another phosphorylation site, T872. Therefore, the question arose as to whether phosphorylation of T872 is involved in downregulating the receptors and whether phosphorylation of this site is also mediated by CaMKIIβ or by another protein kinase. Here, we show that mutational inactivation of T872 in GABAB1 prevented the degradation of the receptors in cultured neurons. We found that, in addition to CaMKIIβ, also ERK1/2 is involved in the degradation pathway of GABAB receptors under physiological and ischemic conditions. In contrast to our previous view, CaMKIIβ does not appear to directly phosphorylate S867. Instead, the data support a mechanism in which CaMKIIβ activates ERK1/2, which then phosphorylates S867 and T872 in GABAB1. Blocking ERK activity after subjecting neurons to ischemic stress completely restored downregulated GABAB receptor expression to normal levels. Thus, preventing ERK1/2-mediated phosphorylation of S867/T872 in GABAB1 is an opportunity to inhibit the pathological downregulation of the receptors after ischemic stress and is expected to restore a healthy neuronal excitation/inhibition balance.ISSN:1422-006

Ca²⁺/Calmodulin-Dependent Protein Kinase II (CaMKII) β-Dependent Phosphorylation of GABAB1 Triggers Lysosomal Degradation of GABAB Receptors via Mind Bomb-2 (MIB2)-Mediated Lys-63-Linked Ubiquitination

The G protein-coupled GABAB receptors, constituted from GABAB1 and GABAB2 subunits, are important regulators of neuronal excitability by mediating long-lasting inhibition. One factor that determines receptor availability and thereby the strength of inhibition is regulated protein degradation. GABAB receptors are constitutively internalized from the plasma membrane and are either recycled to the cell surface or degraded in lysosomes. Lys-63-linked ubiquitination mediated by the E3 ligase Mind bomb-2 (MIB2) is the signal that sorts GABAB receptors to lysosomes. However, it is unknown how Lys-63-linked ubiquitination and thereby lysosomal degradation of the receptors is regulated. Here, we show that Ca2+/calmodulin-dependent protein kinase II (CaMKII) promotes MIB2-mediated Lys-63-linked ubiquitination of GABAB receptors. We found that inhibition of CaMKII in cultured rat cortical neurons increased cell surface GABAB receptors, whereas overexpression of CaMKIIβ, but not CaMKIIα, decreased receptor levels. This effect was conveyed by Lys-63-linked ubiquitination of GABAB1 at multiple sites mediated by the E3 ligase MIB2. Inactivation of the CaMKII phosphorylation site on GABAB1(Ser-867) strongly reduced Lys-63-linked ubiquitination of GABAB receptors and increased their cell surface expression, whereas the phosphomimetic mutant GABAB1(S867D) exhibited strongly increased Lys-63-linked ubiquitination and reduced cell surface expression. Finally, triggering lysosomal degradation of GABAB receptors by sustained activation of glutamate receptors, a condition occurring in brain ischemia, was accompanied with a massive increase of GABAB1(Ser-867) phosphorylation-dependent Lys-63-linked ubiquitination of GABAB receptors. These findings indicate that CaMKIIβ-dependent Lys-63-linked ubiquitination of GABAB1 at multiple sites controls sorting of GABAB receptors to lysosomes for degradation under physiological and pathological condition

Constitutive, agonist-accelerated, recycling and lysosomal degradation of GABA(B) receptors in cortical neurons

Endocytosis is considered as an important mechanism for regulating cell surface numbers and thereby signaling strength of G protein-coupled receptors. Currently, little is known about the endocytotic pathways of GABA(B) receptors in neurons. Here we report that GABA(B) receptors are constitutively internalized presumably via clathrin-dependent endocytosis in cultured cortical neurons. Colocalization of GABA(B) receptors with endosomal marker proteins indicated sorting of GABA(B) receptors from early endosomes to recycling endosomes and to lysosomes. Cell surface biotinylation experiments revealed fast constitutive recycling of GABA(B) receptors as the predominant pathway that was accelerated by the GABA(B) receptor agonist baclofen. Finally, degradation of GABA(B) receptors in lysosomes was demonstrated by their intracellular accumulation upon inhibition of lysosomal proteases and by blocking recycling which resulted in the redirection of receptors to lysosomes for degradation. These data imply rapid constitutive - agonist-accelerated - recycling of GABA(B) receptors presumably via clathrin-coated pits and their final targeting to lysosomes for degradation

Expression of immunoglobulin constant domain genes in neurons of the mouse central nervous system

General consensus states that immunoglobulins are exclusively expressed by B lymphocytes to form the first line of defense against common pathogens. Here, we provide compelling evidence for the expression of two heavy chain immunoglobulin genes in subpopulations of neurons in the mouse brain and spinal cord. RNA isolated from excitatory and inhibitory neurons through ribosome affinity purification revealed Ighg3 and Ighm transcripts encoding for the constant (Fc), but not the variable regions of IgG3 and IgM. Because, in the absence of the variable immunoglobulin regions, these transcripts lack the canonical transcription initiation site used in lymphocytes, we screened for alternative 5' transcription start sites and identified a novel 5' exon adjacent to a proposed promoter element. Immunohistochemical, Western blot, and in silico analyses strongly support that these neuronal transcripts are translated into proteins containing four Immunoglobulin domains. Our data thus demonstrate the expression of two Fc-encoding genes Ighg3 and Ighm in spinal and supraspinal neurons of the murine CNS and suggest a hitherto unknown function of the encoded proteins

Sustained Glutamate Receptor Activation Down-regulates GABAB Receptors by Shifting the Balance from Recycling to Lysosomal Degradation*

Metabotropic GABAB receptors are abundantly expressed at glutamatergic synapses where they control excitability of the synapse. Here, we tested the hypothesis that glutamatergic neurotransmission may regulate GABAB receptors. We found that application of glutamate to cultured cortical neurons led to rapid down-regulation of GABAB receptors via lysosomal degradation. This effect was mimicked by selective activation of AMPA receptors and further accelerated by coactivation of group I metabotropic glutamate receptors. Inhibition of NMDA receptors, blockade of L-type Ca2+ channels, and removal of extracellular Ca2+ prevented glutamate-induced down-regulation of GABAB receptors, indicating that Ca2+ influx plays a critical role. We further established that glutamate-induced down-regulation depends on the internalization of GABAB receptors. Glutamate did not affect the rate of GABAB receptor endocytosis but led to reduced recycling of the receptors back to the plasma membrane. Blockade of lysosomal activity rescued receptor recycling, indicating that glutamate redirects GABAB receptors from the recycling to the degradation pathway. In conclusion, the data indicate that sustained activation of AMPA receptors down-regulates GABAB receptors by sorting endocytosed GABAB receptors preferentially to lysosomes for degradation on the expense of recycling. This mechanism may relieve glutamatergic synapses from GABAB receptor-mediated inhibition resulting in increased synaptic excitability

Subtype-selective interaction with the transcription factor CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) regulates cell surface expression of GABA(B) receptors

The metabotropic gamma-aminobutyric acid, type B (GABA(B)) receptors mediate the slow component of GABAergic transmission in the brain. Functional GABA(B) receptors are heterodimers of the two subunits GABA(B1) and GABA(B2), of which GABA(B1) exists in two main isoforms, GABA(B1a) and GABA(B1b). The significance of the structural heterogeneity of GABA(B) receptors, the mechanism leading to their differential targeting in neurons as well as the regulation of cell surface numbers of GABA(B) receptors, is poorly understood. To gain insights into these processes, we searched for proteins interacting with the C-terminal domain of GABA(B2). Here, we showed that the transcription factor CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) directly interacts with GABA(B) receptors in a subtype-selective manner to regulate cell surface expression of GABA(B1a)/GABA(B2) receptors upon co-expression in HEK 293 cells. The interaction of CHOP with GABA(B1a)/GABA(B2) receptors resulted in their intracellular accumulation and in a reduced number of cell surface receptors. This regulation required the interaction of CHOP via two distinct domains with the heterodimeric receptor; its C-terminal leucine zipper associates with the leucine zipper present in the C-terminal domain of GABA(B2), and its N-terminal domain associates with an as yet unidentified site on GABA(B1a). In conclusion, the data indicated a subtype-selective regulation of cell surface receptors by interaction with the transcription factor CHOP

Expression of immunoglobulin constant domain genes in neurons of the mouse central nervous system

General consensus states that immunoglobulins are exclusively expressed by B lymphocytes to form the first line of defense against common pathogens. Here, we provide compelling evidence for the expression of two heavy chain immunoglobulin genes in subpopulations of neurons in the mouse brain and spinal cord. RNA isolated from excitatory and inhibitory neurons through ribosome affinity purification revealed Ighg3 and Ighm transcripts encoding for the constant (Fc), but not the variable regions of IgG3 and IgM. Because, in the absence of the variable immunoglobulin regions, these transcripts lack the canonical transcription initiation site used in lymphocytes, we screened for alternative 5′ transcription start sites and identified a novel 5′ exon adjacent to a proposed promoter element. Immunohistochemical, Western blot, and in silico analyses strongly support that these neuronal transcripts are translated into proteins containing four Immunoglobulin domains. Our data thus demonstrate the expression of two Fc-encoding genes Ighg3 and Ighm in spinal and supraspinal neurons of the murine CNS and suggest a hitherto unknown function of the encoded proteins.ISSN:2575-107