In this regard, microtubule-associated proteins MAPs play a very important role. Members of this group of proteins, such as MAP2 and tau, are known to promote MT assembly and stabilize MTs in vivo and in vitro [ 10 — 13 ]. The phosphorylation of MAPs is critical for their function, since phosphorylated MAPs separate from MTs, causing MTs to become more susceptible to disassembly and destabilization [ 14 , 15 ].
Also, many drugs known to alter tubulin polymerization are considered valuable tools in studying the mechanisms of MT assembly. Some of these drugs, such as nocodazole, depolymerize MTs, whereas others, such as taxol, promote MT assembly [ 18 — 21 ]. Although much progress has been made in identifying and characterizing the cellular factors that regulate MT assembly and dynamics, the precise spatial and temporal control of the process is not clearly understood.
Over the past decades, an effort has been made to understand the regulation of MT assembly and dynamics by signal transducing G proteins, as reviewed in Refs. GPCRs participate in the regulation of a wide variety of physiological functions, including cell growth and differentiation, neurotransmission, immune system function, and hormonal signaling.
GPCRs consist of seven transmembrane domains, connected by three extracellular loops and three intracellular loops. The extracellular region is responsible for agonist binding neurotransmitters, hormones, and odorants, among others , and the intracellular region is responsible for interacting with heterotrimeric G proteins [ 30 ]. G-protein-mediated signaling and the regulation of MT assembly.
It is suggested that G-protein-MT interaction is an important step for G-protein-mediated cell activation. Although G proteins are likely to be membrane-bound when coupled to receptors, results from several laboratories in past decades demonstrate their association with several subcellular compartments including MTs. This chapter focuses on our current understanding of G protein regulation of MT assembly and cellular and physiological aspects of this regulation. Assembly was monitored by negative staining electron microscopy and measuring protein in polymers collected by centrifugation.
Colchicine and the synthetic compound nocodazole are both antimitotic drugs and known to exert their effects by a similar mechanism, that is, by binding to tubulin dimers and inhibiting the subsequent addition of tubulin molecules to microtubules. However, the potential usefulness of nocodazole is due to its readily reversible and rapid activity [ 53 , 54 ].
This result was further confirmed by the isolation of polymerized tubulin MT and soluble tubulin ST fractions from PC12 cells.
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Microtubules in PC12 cells are well defined and extend to the cell periphery. In addition, lipid-modified, G-protein subunits have been shown to reconstitute heterotrimers more effectively [ 61 , 62 ]. In doing so, GPCRs may control a variety of cellular activities. It appears that G-protein-MT interaction is an important step for G-protein-mediated cell activation. Microtubules play a key role in cell division, participating in the exact organization and function of the spindle apparatus, a vehicle necessary for chromosomal segregation.
Microtubules in the spindle are organized in such a way that the minus ends are near the spindle poles, while the plus ends extend toward the cell cortex or chromosomes [ 63 ]. Genetic studies in C. Recently, it has been shown that reconstituted kinetochores in vitro bind preferentially to GTP rather than to GDP microtubules, suggesting that a protein exists in kinetochores that can distinguish between GTP conformation of the microtubules and allow the kinetochores to remain at the microtubule ends to ensure correct chromosome segregation [ 72 ].
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The process by which MT structure is remodeled in neurons is a central question in cell biology and recent research indicates an important role of G protein subunits in this process. During neuronal differentiation, two distinct domains emerge from the cell body: a long, thin axon that transmits signals, and multiple shorter dendrites, which are specialized primarily for receiving signals. The axon terminal contains synapses, specialized structures where neurotransmitters are released to communicate with target neurons. Cytoskeletal structures embodied within neurite extensions and growth cone formations are essential for establishing appropriate synaptic connections and signal transmission.
MTs form dense parallel arrays in axons and dendrites that are required for the growth and maintenance of such neurites. In the axon, MTs are bundled by tau, a microtubule-associated protein MAP , with their plus end oriented toward the nerve terminal.
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Unlike MTs, actin filaments in neurons are enriched in growth cones and organized into long bundles that form filamentous protrusions, or filopodia, veil-like sheets of branched actin that form lamellipodia [ 1 , 7 , 73 ]. The interaction between these two cytoskeletal filaments is important for the advancement of growth cones and axon guidance [ 74 , 75 ]. Neuronal cytoskeleton. The polarized and asymmetrical shape of neurons is achieved by means of a highly specialized cytoskeletal organization. In addition to cell body, MTs are found in the axon, dendrites, and the central domain of the growth cone.
Actin filaments are present in the growth cone and dendrites, where they form specialized structures such as lamellipodia and filopodia. It is clear that cytoskeletal components can detect biochemical signals and respond in order to change the neuronal cell morphology. However, the precise signaling pathways that lead unique organization of MTs in neurons are not clearly understood [ 76 ].
PC12 cells have been used extensively for these studies as they respond to nerve growth factor NGF with growth arrest and exhibit a typical phenotype of neuronal cells that send out neurites [ 77 ]. NGF is a neurotrophic factor critical for the survival and maintenance of sensory and sympathetic neurons. The receptor commonly associated with this process is tyrosine kinase TrkA through which NGF exerts its effect [ 78 ].
Biological functions of microtubules and related structures
Sachdev et al. To address this, PC12 cells were treated with NGF over the course of three days to allow for neuronal differentiation. Microtubules MTs and soluble tubulin ST fractions were extracted using a microtubule-stabilizing buffer.
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