Calcium/calmodulin-dependent protein kinase kinase 2 is an enzyme that in humans is encoded by the CAMKK2 gene. [5] [6]
Calcium/calmodulin-dependent protein kinase kinase 2 is an enzyme that in humans is encoded by the CAMKK2 gene. [5] [6]
The product of this gene belongs to the serine/threonine-specific protein kinase family, and to the Ca++/calmodulin-dependent protein kinase subfamily. This protein plays a role in the calcium/calmodulin-dependent (CaM) kinase cascade by phosphorylating the downstream kinases CaMK1 and CaMK4, [6] which increases their catalytic activity. [7] CaMK1 and CaMK4 are phosphorylated at the Thr 177 and Thr 196 resides respectively. [8] [9]
CaMKK2 regulates production of the appetite stimulating hormone neuropeptide Y and functions as an AMPK kinase in the hypothalamus. [10] It also has an important role in the development of hyperalgesia and tolerance to opioid analgesic drugs, through reduction in downstream signalling pathways and mu opioid receptor downregulation. [11] [12] [13] Inhibition of CaMKK2 in mice reduces appetite and promotes weight loss. [10]
CaMKK2 has several functions in different brain regions. In the hippocampus, the CaMKK2/CaMK1 cascade is necessary for memory formation through the regulation of learning-induced structural changes in the neuronal cytoskeleton. [14] [15] Morphological changes in dendritic spines in the hippocampus - which are necessary for initiating and maintaining the synaptic plasticity in CA1 pyramidal neurons - are the main structural basis for the formation of memories. [16] [15]
The CaMKK2/CaMKIV/CREB cascade is involved in the postnatal development of the cerebellum. CaMKK2 deletion impairs development of Cerebellar Granule Cells -the most abundant cells in the cerebellum- by inhibiting the ability of Granule Cell Precursors (GCPs) to stop proliferating in the external granule layer (EGL) and migrate to the internal granule layer. [17] [18] [19] This phenotype is also tied to reduced BDNF expression and decreased CREB phosphorylation. Thus, the CaMKK2/CaMKIV/CREB cascade is required for BDNF (Brain Derived Neurotrophic Factor) production in the post-natal cerebellum in order to complete an important step of CGC development. [15] Neuronal CaMKK2's regulation of BDNF was recently implicated in progression of Glioblastoma. [20]
In the hypothalamus, CaMKK2 is involved in centrally mediating energy homeostasis by forming a signaling complex with AMPKα/β and Ca2+/CaM. [10] [15] Genetic ablation of CaMKK2 decreases AMPK [21] activity in hypothalamus and down regulates NPY and AgRP gene expression in NPY Neurons, which has been shown to protect mice from diet-induced obesity, hyperglycemia, and insulin resistance. [10] Additionally, CaMKK2 is involved in the genetic regulation of genes necessary for optimal sympathetic activity in the medial hypothalamus, and therefore bone mass accrual, which can be said to be negatively associated to sympathetic tone. [22] [15]
Seven transcript variants encoding six distinct isoforms have been identified for this gene. Additional splice variants have been described but their full-length nature has not been determined. The identified isoforms exhibit a distinct ability to undergo autophosphorylation and to phosphorylate the downstream kinases. [6] [23]
CREB-TF is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. CREB was first described in 1987 as a cAMP-responsive transcription factor regulating the somatostatin gene.
CAMK, also written as CaMK or CCaMK, is an abbreviation for the Ca2+/calmodulin-dependent protein kinase class of enzymes. CAMKs are activated by increases in the concentration of intracellular calcium ions (Ca2+) and calmodulin. When activated, the enzymes transfer phosphates from ATP to defined serine or threonine residues in other proteins, so they are serine/threonine-specific protein kinases. Activated CAMK is involved in the phosphorylation of transcription factors and therefore, in the regulation of expression of responding genes. CAMK also works to regulate the cell life cycle (i.e. programmed cell death), rearrangement of the cell's cytoskeletal network, and mechanisms involved in the learning and memory of an organism.
Ca2+
/calmodulin-dependent protein kinase II is a serine/threonine-specific protein kinase that is regulated by the Ca2+
/calmodulin complex. CaMKII is involved in many signaling cascades and is thought to be an important mediator of learning and memory. CaMKII is also necessary for Ca2+
homeostasis and reuptake in cardiomyocytes, chloride transport in epithelia, positive T-cell selection, and CD8 T-cell activation.
CAMP responsive element binding protein 1, also known as CREB-1, is a protein that in humans is encoded by the CREB1 gene. This protein binds the cAMP response element, a DNA nucleotide sequence present in many viral and cellular promoters. The binding of CREB1 stimulates transcription.
Calcium/calmodulin-dependent protein kinase type II subunit alpha (CAMKIIα), a.k.a.Ca2+/calmodulin-dependent protein kinase II alpha, is one subunit of CamKII, a protein kinase (i.e., an enzyme which phosphorylates proteins) that in humans is encoded by the CAMK2A gene.
Dual specificity mitogen-activated protein kinase kinase 6 also known as MAP kinase kinase 6 or MAPK/ERK kinase 6 is an enzyme that in humans is encoded by the MAP2K6 gene, on chromosome 17.
Dual specificity mitogen-activated protein kinase kinase 3 is an enzyme that in humans is encoded by the MAP2K3 gene.
Calcium/calmodulin-dependent protein kinase type II beta chain is an enzyme that in humans is encoded by the CAMK2B gene.
Cyclic AMP-dependent transcription factor ATF-1 is a protein that in humans is encoded by the ATF1 gene.
Peripheral plasma membrane protein CASK is a protein that in humans is encoded by the CASK gene. This gene is also known by several other names: CMG 2, calcium/calmodulin-dependent serine protein kinase 3 and membrane-associated guanylate kinase 2. CASK gene mutations are the cause of XL-ID with or without nystagmus and MICPCH, an X-linked neurological disorder.
Calcium/calmodulin-dependent protein kinase type IV is an enzyme that in humans is encoded by the CAMK4 gene.
Calcium/calmodulin-dependent protein kinase type II gamma chain is an enzyme that in humans is encoded by the CAMK2G gene.
Dual specificity mitogen-activated protein kinase kinase 7, also known as MAP kinase kinase 7 or MKK7, is an enzyme that in humans is encoded by the MAP2K7 gene. This protein is a member of the mitogen-activated protein kinase kinase family. The MKK7 protein exists as six different isoforms with three possible N-termini and two possible C-termini.
Calcium/calmodulin-dependent protein kinase type 1 is an enzyme that in humans is encoded by the CAMK1 gene.
Calcium/calmodulin-dependent protein kinase type II delta chain is an enzyme that in humans is encoded by the CAMK2D gene.
Calcium/calmodulin-dependent protein kinase kinase 1 is an enzyme that in humans is encoded by the CAMKK1 gene.
Cyclin-dependent kinase 5 activator 2 is an enzyme that in humans is encoded by the CDK5R2 gene.
cGMP-dependent protein kinase 1, alpha isozyme is an enzyme that in humans is encoded by the PRKG1 gene.
Mitogen-activated protein kinase 11 is an enzyme that in humans is encoded by the MAPK11 gene.
Activity-regulated cytoskeleton-associated protein is a plasticity protein that in humans is encoded by the ARC gene. It was first characterized in 1995. ARC is a member of the immediate-early gene (IEG) family, a rapidly activated class of genes functionally defined by their ability to be transcribed in the presence of protein synthesis inhibitors. ARC mRNA is localized to activated synaptic sites in an NMDA receptor-dependent manner, where the newly translated protein is believed to play a critical role in learning and memory-related molecular processes. Arc protein is widely considered to be important in neurobiology because of its activity regulation, localization, and utility as a marker for plastic changes in the brain. Dysfunction in the production of Arc protein has been implicated as an important factor in understanding various neurological conditions, including amnesia, Alzheimer's disease, Autism spectrum disorders, and Fragile X syndrome. Along with other IEGs such as ZNF268 and HOMER1, ARC is also a significant tool for systems neuroscience as illustrated by the development of the cellular compartment analysis of temporal activity by fluorescence in situ hybridization, or catFISH technique.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.